Gut microbiota shapes cancer immunotherapy responses.

Introduction

In 2001, the concept of “microbial community” was first introduced, which mainly consists of 40 trillion microorganisms, including bacteria, fungi, archaea, and viruses, with more than 100 times as many genes as the human genome 1 – 4 . Among them, the gut microbiota is particularly significant, colonizing the colon and comprising over 97% of the total microbial population 2 , 5 . Given that it contains up to 60-70% of peripheral immune cells and interacts with a substantial number of microbiota, the gut is regarded as the largest peripheral immune organ in the body 6 , 7 . These microorganisms help maintain intestinal homeostasis through metabolic and immune-mediated pathways, influencing key physiological processes such as metabolism, inflammation, immunity, and neurology 8 – 10 . For instance, microbial metabolites such as short-chain fatty acids (SCFAs) and bile acids (BAs) play crucial roles in shaping both innate and adaptive immune responses 11 – 13 .

Disruptions in gut microbial composition have been linked to cancer development through multiple mechanisms, including genomic instability, alterations in the tumor microenvironment, and modulation of immune evasion strategies 14 , 15 . Malignant tumors remain the second leading cause of death globally, and while conventional treatments like chemotherapy, radiotherapy, and surgery have improved patient outcomes, they are often limited by drug resistance, recurrence, and adverse side effects. In recent years, immunotherapies—such as immune checkpoint inhibitors (ICIs) and adoptive cell transfer therapies (ACTs)—have revolutionized cancer treatment 16 , 17 . However, responses to these therapies vary significantly among patients, with some exhibiting primary or acquired resistance, underscoring the need for novel adjuvant approaches 18 – 20 .

In recent years, the influence of the gut microbiota on tumorigenesis and therapeutic response has been gradually uncovered with the help of next-generation sequencing (NGS) and third-generation sequencing technologies 21 – 23 . Specific microbial compositions not only differentiate cancer patients from healthy individuals but also correlate with immunotherapy outcomes, making them potential biomarkers for predicting treatment efficacy 24 , 25 . Strategies to modulate gut microbiota—such as fecal microbiota transplantation (FMT), probiotics, prebiotics, and dietary interventions—have shown promise in enhancing immunotherapy response and mitigating treatment-related toxicity 26 – 30 . Additionally, tumor-associated microbiota within the tumor microenvironment (TME) may influence therapeutic outcomes by modulating inflammation, promoting immune cell infiltration, and enhancing drug-induced immunogenic cell death 31 – 33 . These findings have opened new avenues for microbiome-based precision oncology.

Despite these advancements, the mechanisms underlying interactions between the gut microbiota and tumor immunity remain incompletely understood, and research on microbiota-driven immunotherapy optimization is still in its early stages. A deeper understanding of the molecular and systems biology functions of gut microbes is critical for identifying novel therapeutic targets and improving clinical applications. In this review, we examine the role of the gut microbiota in shaping immunotherapy efficacy, focusing on ICIs and ACTs, and exploring its impact on treatment-related toxicity. We also discuss emerging microbiota-targeted interventions and personalized therapeutic strategies, highlighting key studies that have advanced the field. Finally, we address current challenges and future perspectives in leveraging gut microbiota for cancer immunotherapy.

The evolving role of gut microbiota in cancer immunotherapy: a historical perspective

Immunotherapies, particularly ICIs and ACTs—including T-cell receptor-engineered T cells (TCR-T) and chimeric antigen receptor T cells (CAR-T)—have transformed cancer treatment and significantly improved patient outcomes 34 – 36 . These therapies work by activating or modulating the immune system to enhance anti-tumor responses. However, their efficacy varies widely across cancer types and patient populations, with key challenges such as antigen escape, limited transport, and insufficient tumor infiltration affecting treatment success 37 – 41 . Additionally, tumor mutation burden (TMB)—the total number of somatic mutations per coding region of a tumor genome—has emerged as a significant biomarker predicting immunotherapy response. Tumors with higher TMB, such as melanoma and non-small-cell lung cancer (NSCLC), tend to generate more neoantigens, thereby enhancing tumor immunogenicity and responsiveness to ICIs 42 . Conversely, cancers with lower TMB, such as prostate and pancreatic cancer, often exhibit reduced neoantigen formation, resulting in limited immune recognition and decreased efficacy of immunotherapies 43 . Emerging clinical studies have identified a strong correlation between gut microbiota composition and immunotherapy outcomes in cancer patients (Fig. 1 and Table 1 ) 44 – 89 . Fecal sample analyses suggest that variations in gut microbial communities may influence treatment efficacy through underlying biological mechanisms. These studies demonstrate the utility of microbiota interventions in clinical practice. However, given the complexity of the gut microbiota and significant individual heterogeneity, translation of microbiota-based insights into clinical practice remains limited. Further investigation is needed to fully elucidate these interactions and harness the gut microbiota to optimize immunotherapy strategies. Fig. 1 Timeline for key advancements of gut microbiota research on immunotherapy. ACT, adoptive cell therapy; PD-L1, programmed cell death ligand 1; CTLA-4, cytotoxic T lymphocyte-associated antigen-4; ICI, immune checkpoint inhibitor; Rs, responders; NRs, non-responders; TME, tumor microenvironment; CAR-T, chimeric antigen receptor T-cell therapy; NGS, next generation sequencing. Early mouse studies (2007–2013) demonstrated that gut microbiota can enhance anti-tumor immune responses, whereas antibiotic treatment attenuates the efficacy of ACT. In 2015, research first revealed a direct relationship between gut microbiota and ICI response, identifying specific bacterial species such as Bifidobacterium and Bacteroides fragilis as promoters of ICI efficacy. Subsequent preclinical and clinical studies in 2018 explored the potential of gut microbiota and its metabolites as predictive markers for the effectiveness of ICIs and ACTs. Clinical breakthroughs between 2020 and 2021 further demonstrated that fecal microbiota transplantation (FMT) could enhance ICI response, while gut microbial metabolites were found to improve the activity of CAR-T cells. More recent retrospective and prospective studies (2022–2023) have established correlations between gut microbiome composition and CAR-T cell therapy efficacy, leveraging next-generation sequencing (NGS) and machine learning algorithms for predictive analysis. In 2024–2025, researchers focus on multi-omics and metabolic mechanisms underlying gut microbiota interactions with immunotherapy. Table 1 Some clinical studies on the impact of the gut microbiome on immunotherapy efficacy Year Immunotherapy type Cancer type Patients number Beneficial clinical outcomes Adverse clinical outcomes Ref. 2016 αCTLA-4 mAb Melanoma 34 Members of Bacteroidetes phylum 44 2018 αPD-1 mAb; αPD-L1 mAb NSCLC; RCC; urothelial carcinoma 249 Akkermansia muciniphila; Clostridiales; Ruminococcaceae 25 2018 αPD-1 mAb Melanoma 112 Ruminococcaceae family 45 2018 αPD-1 mAb Melanoma 42 Bifidobacterium longum; Collinsella aerofaciens; Enterococcus faecium 46 2019 αPD-1 mAb; αPD-L1 mAb; αCTLA-4 mAb Melanoma 27 Faecalibacterium prausnitzii; Coprococcus eutactus; Prevotella stercorea; Streptococcus sanguinis; Streptococcus anginosus; Lachnospiraceae bacterium Bacteroides ovatus; Bacteroides dorei; Bacteroides massiliensis; Ruminococcus gnavus; Blautia producta 47 2019 αPD-1 mAb NSCLC 17 Lactobacillus; Clostridium; Syntrophococcus Bilophila; Sutterella; Parabacteroides 48 2019 αPD-1 mAb NSCLC 37 Alistipes putredinis; Bifidobacterium longum; Prevotella copri 49 2019 αPD-1 mAb HCC 18 Akkermansia muciniphila; Ruminococcaceae spp. 50 2020 αPD-1 mAb; αPD-L1 mAb; αCTLA-4 mAb Melanoma 130 Faecalibacterium; Ruminococcaceae; Barnesiella intestinihominis 51 2020 αPD-1 mAb NSCLC 11 Akkermansia muciniphila; Rikenellaceae; Bacteroides; Peptostreptococcaceae; Mogibacteriaceae; Clostridiaceae 52 2020 αPD-1 mAb; αPD-L1 mAb; Gastrointestinal cancer 74 Prevotella; Ruminococcaceae; Lachnospiraceae 53 2020 αPD-1 mAb RCC 21 Akkermansia muciniphila 54 2021 αPD-1 mAb Melanoma 10 Enterococcaceae; Enterococcus; Streptococcus australis Veillonella atypica 26 2021 αPD-1 mAb Melanoma 438 Ruminococcaceae 28 2021 αPD-1 mAb Melanoma 15 Firmicutes (Lachnospiraceae and Ruminococcaceae families) and Actinobacteria (Bifidobacteriaceae and Coriobacteriaceae families) Bacteroidetes phylum 55 2021 αPD-1 mAb combined with αCTLA-4 mAb Melanoma 77 Bacteroides intestinalis 56 2021 αPD-1 mAb NSCLC 294 Bifidobacterium; Clostridium butyricum; Lactic acid bacteria 57 2021 ICI Lung cancer 34 Clostridiales Rikenellaceae 58 2021 αPD-1 mAb Hepatobiliary cancers 65 Lachnospiraceae bacterium-GAM79; Alistipes sp. Marseille-P5997; Ruminococcus calidus; Erysipelotichaceae bacterium GAM147 Veillonellaceae 59 2021 αPD-1 mAb HCC 11 Citrobacter freundii; Azospirillum sp.; Enterococcus durans; Akkermansia; 60 2021 ACT combined with chemotherapy CRC 39 Bifidobacterium; Lactobacillus; Enterococcus Dialister pneumosintes; Escherichia coli; Lactobacillus reteri; Streptococcus mutans; Enterococcus faecium; Streptococcus gordonii; Veillonella atypica; Granulicatella sp.; Trchuris trichiura 61 2021 αPD-1 mAb Thoracic neoplasms 42 Akkermansiaceae; Enterococcaceae; Enterobacteriaceae; Carnobacteriaceae; Clostridiales Family XI bacterial families 62 2022 αPD-1 mAb; αCTLA-4 mAb Cutaneous melanoma 165 Bifidobacterium pseudocatenulatum; Roseburia spp.; Akkermansia muciniphila Rumminococcus torques; Escherichia coli; Klebsiella pneumoniae 63 2022 αPD-1 mAb Melanoma 94 Actinobacteria phylum; Lachnospiraceae; Ruminococcaceae; Lachnospiraceae spp.; Streptococcaceae spp. 64 2022 αPD-1 mAb combined with αCTLA-4 mAb Melanoma 218 Ruminococcaceae Bacteroidaceae 65 2022 αPD-1 mAb; αPD-L1 mAb; αCTLA-4 mAb NSCLC 65 Ruminococcus; Akkermansia; Faecalibacterium 66 2022 αPD-1 mAb Lung cancer 46 Fusobacterium 67 2022 αPD-1 mAb HCC 41 Lachnoclostridium; Lachnospiraceae; Veillonella Prevotella 9 68 2022 αPD-1 mAb; αPD-L1 mAb; Gastric cancer 74 Prevotella; Ruminococcaceae; Lachnospiraceae 69 2022 ICI combined with enzalutamide CRPC 23 Streptococcus salivarius Akkermansia muciniphila; Collinsella aerofaciens 70 2022 Anti-CD19 CAR-T B cell lymphoma; leukemia 48 Ruminococcus; Bacteroides; Faecalibacterium; Akkermansia 71 2022 CAR-T MM; ALL; NHL 78 Faecalibacterium; Roseburia; Ruminococcus 72 2022 αPD-1 mAb NPC 57 Blautia wexlera; Blautia obeum; Erysipelatoclostridium; Ruminococcaceae bacterium; Ruminococcus sp. AF46-10NS 73 2023 αPD-1 mAb Melanoma 20 Ruminococcaceae; Alistipes communis; Blautia Enterocloster asparagiformis; Catabacter hongkongensis 74 2023 αPD-1 mAb NSCLC 62 Alistipes; Barnesiella Multiple Streptococcus; Bifidobacteria 75 2023 ICI Lung cancer 50 Akkermansia muciniphila; Alistipes onderdonkii; Ruminococcus taxa 76 2023 αPD-1 mAb; αPD-L1 mAb; Gastric cancer Lactobacillus; Erysipelotrichaceae; Ruminooccus; Eubacterium Streptococcus spp 77 2023 αPD-1 mAb CRC 20 Proteobacteria Actinobacteriota 78 2023 Anti-CD19 CAR-T B cell lymphoma 172 Akkermansia muciniphila; Ruminococcus lactaris; Lachnospira pectinoschiza; Bacteroides eggerthii Bacteroides uniformis; Bacteroides ovatus; Blautia spp.; Faecalibacterium prausnitzii; Firmicutes bacterium CAG 424 79 2024 αPD-1 mAb; αCTLA-4 mAb Melanoma 175 Agathobaculum butyriciproducens; Intestinibacter bartlettii; Dorea sp. AF24 7LB; Lactobacillus gasseri; Lacrimispora celerecrescens Ruthenibacterium lactatiformans; Prevotella copri clade A; Ruminococcaceae unclassified; Bacteroidete phylum 80 2024 αPD-1 mAb; αPD-L1 mAb SCLC 49 Akkermansia muciniphila; Bifidobacterium bifidum; two Roseburia species; three Blautia species Erysipelatoclostridium ramosum; Enterococcus faecalis 81 2024 ICI NSCLC 95 Firmicutes; Ruminococcaceae Intestinimonas; Enterobacteriacea 82 2024 αPD-1 mAb Rectal cancer 33 Lachnospiraceae bacterium; Blautia wexlerae Bacteroides; Prevotella; Porphyromonas 83 2024 αPD-L1 mAb combined with bevacizu-mab Mesothelioma 26 Prevotella; Butyricioccus; Eubacterium ventriosum Erysipeloclostridium 84 2024 αPD-1 mAb combined with bevacizumab and chemotherapy OC 40 Intestinimonas butyriciproducens; Anaerotignum propionicum (Clostridium propionicum) Enterococcus faecalis; Clostridium perfringens 85 2024 TLR agonists combined with αPD-1 mAb Melanoma 31 Firmicutes; Actinobacteria phyla Proteobacteria; Bacteroidetes 86 2024 αPD-1 mAb Gastric cancer 30 Akkermansia muciniphila; Dorea formicigenerans 87 2025 αPD-1 mAb Melanoma 23 Clostridia (Bacillota/Firmicutes phylum, 77%) Bacteroidales (Bacteroidetes phylum, 60%) and Clostridiales (40%) 88 2025 αPD-1 mAb; αPD-L1 mAb; NPC 17 Lachnoclostridium; Actinobacillus; Anaerotruncus; Moraxellaceae; Sellimonas 89 NSCLC non-small-cell lung cancer, HCC hepatocellular carcinoma, RCC renal cell carcinoma, CRC colorectal cancer, CRPC castration-resistant prostate cancer, MM multiple myeloma, ALL acute lymphoblastic leukemia, NHL non-Hodgkin lymphoma; SCLC small cell lung cancer, OC ovarian cancer, NPC nasopharyngeal carcinoma.

Gut microbiota and ICIs: modulation, response and therapeutic potential

ICIs work by enhancing the body’s immune response against tumors, primarily by blocking inhibitory immune checkpoints such as programmed cell death protein 1 (PD-1), its ligand PD-L1, and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). Currently, ICIs have been widely used in the treatment of a variety of cancers. Apart from mismatch repair deficient (dMMR) colorectal cancer, which is consistently responsive to ICIs, in general, only 20-40% of patients (including the most responsive tumor types such as melanoma, lung cancer and renal cell carcinoma) are susceptible to ICIs 45 , 46 . Early preclinical research suggested that gut microbiota plays a key role in modulating anti-tumor immune responses 90 – 92 . In 2015, Sivan et al. first reported that commensal bacteria influence both spontaneous immune responses to tumors and the effectiveness of ICIs 93 . They demonstrated that oral administration of Bifidobacterium enhanced the anti-tumor efficacy of PD-L1 inhibitors by promoting dendritic cell (DC) maturation and increasing tumor-specific CD8 + T cell activity. Another study that same year showed that antibiotic treatment could reduce the effectiveness of ICIs, while supplementation with Bacteroides fragilis in melanoma models restored anti-CTLA-4 efficacy by stimulating Th1 cell activation in tumor-draining lymph nodes and enhancing intra-tumoral dendritic cell maturation 94 .

By 2018, clinical trials confirmed that gut microbiota composition and diversity could predict ICI response 25 , 45 . Patients with non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) who had higher gut microbial diversity responded better to anti-PD-1 therapy 25 . In metastatic melanoma, responders exhibited increased levels of Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium, and fecal microbiota transplantation (FMT) from these patients into germ-free mice improved anti-PD-L1 therapy outcomes 45 . Retrospective studies further linked antibiotic use to reduced ICI efficacy and lower survival rates in patients with advanced solid tumors, reinforcing the role of gut microbiota in shaping anti-tumor immune responses 95 , 96 . Prospective studies have since demonstrated significant correlations between microbiome composition and ICI outcomes in melanoma, NSCLC, and hepatocellular carcinoma (HCC) 46 – 49 . Notably, researchers showed that FMT from ICI responders, combined with anti-PD-1 therapy, could overcome resistance in patients with refractory melanoma 55 , 74 . The first phase I FMT clinical trial further highlighted the role of gut microbiota in modulating responses to anti-PD-1 therapy 54 . Researchers then focused on multi-omics and metabolite mechanisms. Zhu et al. characterized five response-associated gut phenotypes through multi-omics analysis, in which the metabolite phenylethyl fluoride was negatively associated with response and shown to attenuate anti-PD-1 efficacy in vivo, elucidating the interplay between gut microbiota, gut metabolome, and immunotherapy response 97 .

Despite concerted efforts by researchers to combine diverse cohorts and expand sample sizes for studying microbiota associated with immunotherapy 63 , identifying consistent beneficial microbial markers remains challenging. This difficulty stems from multiple confounding factors, including individual and environmental variability, differences in clinical trial design, and methodological inconsistencies. Moreover, gut microbiota linked to response varies by ICI type—bacteria associated with anti-PD-1 and anti-PD-L1 efficacy may differ from those influencing anti-CTLA-4 response, reflecting distinct mechanisms of immune modulation 54 , 93 , 98 . For example, Gunjur et al. suggest that future development of gut microbiota diagnostics or therapeutics should be tailored to ICB treatment protocols rather than to cancer type. Tumor type further influences microbiome interactions, resulting in variability among patients 99 – 101 . For example, in advanced melanoma, high levels of Bifidobacterium, Coriobacteriaceae, Ruminococcaceae, and Lachnospiraceae correlate with favorable anti-PD-1 responses 25 , 45 – 47 , 62 . In contrast, NSCLC, RCC, and HCC patients with greater abundance of Akkermansia muciniphila exhibit improved anti-PD-1 efficacy 25 , 102 . Interestingly, Akkermansia muciniphila has also been linked to resistance in antibiotic-treated patients, suggesting a dual role in ICI response 103 . Most studies to date have relied on metagenomic sequencing of fecal samples to identify microbial species associated with ICI response. However, a comprehensive analysis at the subspecies or strain level has yet to be conducted. Recent studies have revealed that two branches of the same bacterial subspecies do not play identical roles in tumorigenesis and progression, which underscore the necessity for finer-grained studies to elucidate the precise interactions between the microbiome and ICI, with the objective of optimizing the effects of immunotherapy 104 .

Gut microbiota and ACTs: influence on efficacy and toxicity

ACTs, refer to collecting and modifying a patient’s immune cells in vitro to enhance their tumor-killing ability before reinfusion into the body, include T-cell receptor (TCR) therapy, chimeric antigen receptor (CAR) T-cell therapy, natural killer (NK) cell therapy, and tumor-infiltrating lymphocyte (TIL) therapy. Many studies have shown that ACTs, particularly CAR-T cell therapy, has demonstrated significant efficacy in hematologic malignancies and melanoma 105 , 106 .

The influence of gut microbiota on ACT efficacy was first discovered in 2007 when researchers found that the broad-spectrum antibiotic ciprofloxacin reduced the therapeutic effectiveness of ACT in mice. This effect was reversed by supplementing bacterial lipopolysaccharide (LPS), which activates the Toll-like receptor (TLR)-4 pathway 107 . Subsequent studies have provided further indirect evidence linking gut microbiota to ACT outcomes. In 2017, a study showed that vancomycin treatment, which increased Proteobacteria while depleting Firmicutes and Bacteroidetes, enhanced ACT efficacy by promoting CD8α + DCs and upregulating interleukin (IL)-12. In contrast, antibiotics such as neomycin and metronidazole, which deplete Gram-negative aerobic and anaerobic bacteria, respectively, impaired ACT efficacy 108 . This suggests that gut microbiota modulation may improve ACT effectiveness. In 2018, it was shown that gut microbiota-mediated bile acid metabolism increased CXCR6 + NKT cells in the liver, contributing to the anti-tumor activity of HCC 109 . In the same year, researchers found that SCFA, another key microbial metabolite, could strengthen anti-tumor immunity of ACT by inhibiting histone deacetylase to increase the cytotoxicity of CD8+ T cells 110 . Since then, researchers have gradually focused on the effects of gut microbial metabolites on the efficacy of ACT and demonstrated these findings 111 – 113 .

During this time, as ACT therapies evolved, several retrospective studies found that gut microbiota were associated with ACT toxicity and had potential as biomarkers. One study analyzing plasma samples from colorectal cancer (CRC) patients treated with ACT and chemotherapy found that responders had significantly higher blood levels of Bifidobacterium, Lactobacillus, and Enterococcus, indicating that the blood microbiome may serve as a biomarker for immunotherapy response 60 . In 2022, Lauren et al. found that patients treated with piperacillin/tazobactam, meropenem, or imipenem/cilastatin (P-I-M) antibiotics within four weeks before CD19-targeted CAR-T therapy had lower survival rates and higher neurotoxicity risks. Sequencing data identified Ruminococcus, Bacteroides, and Faecalibacterium as key microbial taxa associated with CAR-T efficacy, with bacterial metabolic pathways such as peptidoglycan synthesis and pentose phosphate metabolism emerging as potential biomarkers for response monitoring 70 . In the same year, Melody et al. found that the composition of the gut microbiota appeared to change at different stages of CAR-T therapy. In multiple myeloma (MM) patients, microbial diversity and abundance varied between those in complete remission (CR) and partial remission (PR), with Bifidobacterium, Prevotella, Sutterella, and Collinsella showing significant fluctuations. Moreover, patients who developed severe cytokine release syndrome (CRS) exhibited higher levels of Bifidobacterium, Leuconostoc, Stenotrophomonas, and Staphylococcus, suggesting a potential role of gut microbes in CAR-T-associated toxicities 71 . Targeted microbiota modulation could offer a strategy to mitigate these side effects.

Additionally, gut microbes can shape TME by promoting chemokine secretion, recruiting tumor-infiltrating T cells, and improving patient prognosis 114 . Notably, intratumoral injection of Escherichia coli MG1655 has been shown to normalize tumor vasculature and reprogram tumor-associated macrophages (TAMs) to the M1 phenotype, leading to increased chemokine CCL5 production and enhanced T cell infiltration of ACTs 115 . This approach, which combined bacterial therapy targeting the interior of solid tumors with ACT targeting the periphery of tumors, successfully eradicated early melanoma and slowed pancreatic tumor progression. Current research on the interaction between gut microbiota and ACTs is still in its early stages, with most studies focused on hematologic malignancies. The role of gut microbiota in ACTs efficacy for solid tumors remains unexplored, and the dominant bacterial species and underlying mechanisms require further investigation. In the future, interventions such as microbiota transplantation or metabolite supplementation before T-cell activation could enhance the effectiveness of ACTs and reduce treatment-related toxicity.

Gut microbiota and CpG-ODN immunotherapy: modulation and clinical implications

Pattern recognition receptors (PRRs) play a crucial role in initiating and sustaining innate immunity. Among them, TLRs, nucleotide-binding oligomeric domain-like receptors (NLRs), and C-type lectin receptors (CLRs) are key mediators 116 . Innate immune cells such as DCs and NK cells express PRRs to detect pathogen-associated molecular patterns, bridging innate and adaptive immune responses. CpG oligodeoxynucleotides (CpG-ODNs), synthetic immunomodulatory agents, enhance immune responses by activating TLR9, thereby stimulating both cellular and humoral immunity 117 , 118 .

Studies have demonstrated the gut microbiota’s essential role in CpG-ODN-based immunotherapy. Guiducci et al. found that CpG-ODN treatment in tumors rapidly shifts macrophages from an immunosuppressive M2 phenotype to a pro-inflammatory M1 state, producing high levels of TNF and IL-12, leading to tumor necrosis. However, this effect was absent in sterile or antibiotic-treated mice, suggesting that gut microbiota–derived LPS activate TLR4, priming myeloid cells in tumors to respond to TLR9 stimulation 119 . Similarly, Iida et al. reported that disrupting the microbiota impaired tumor responses to CpG-ODNs and platinum-based chemotherapy 120 . Their findings linked specific bacterial species to TNF production, where Gram-negative Ruminococcus (e.g., A. shahii) enhanced TNF expression, while Gram-positive Lactobacillus species (e.g., L. murinum, L. intestinalis, L. fermentum) were negatively associated. Notably, restoring A. shahii in antibiotic-treated mice reinstated TNF production, underscoring the microbiota’s role in mediating immune responses. The influence of gut microbiota on CpG-ODN immunotherapy has been further validated in clinical trials. A phase II study in melanoma patients receiving CpG-ODN combined with ICIs revealed that responders had an enriched population of Gram-negative Bacteroidaceae, Enterobacteriaceae, and Firmicutes, reinforcing the microbiota’s role in modulating bone marrow-derived immune functions within the TME 85 .

Although the precise mechanisms linking gut microbiota to tumor immunotherapy remain under investigation, emerging research suggests that distinct microbial subtypes influence clinical outcomes, with shared genetic traits modulating host immune responses 62 . Future studies should focus on identifying key bacterial strains and their metabolites to develop targeted microbiota-based strategies for enhancing immunotherapy efficacy.

Gut microbiota and cancer immunotherapy: mechanisms of immune modulation

As mentioned earlier, gut microbes can modulate immunotherapy responses, and the mechanisms by which gut microbiota modulate anti-tumor immune responses also have important implications, with roles involving the immunomodulation of the body, including the immune system and the TME, by the microbiota, either directly or through its metabolites, and by exerting interactions with immunotherapy (Fig. 2 ). Fig. 2 Gut microbiota exert intrinsic and adaptive immunity in the gut and TME. DC, dendritic cell; MHC-I, major histocompatibility complex class I; MHC-II, major histocompatibility complex class II; TCR, T cell receptor; PRR, pattern recognition receptor; NK, natural killer; CTL, cytotoxic T lymphocyte. Within the gut, the gut microbiota plays a crucial role in maintaining the intestinal barrier, protecting against pathogens, and shaping immune responses. Certain bacterial species, such as Bifidobacterium and Bacteroides fragilis, can interacting with DCs and activate CD8 + T cells and Th1 cells. Additionally, invasive microbiota and microbiota-derived metabolites—including lipopolysaccharides (LPS) and peptidoglycans—activate PRRs, promoting macrophage polarization toward the pro-inflammatory M1 phenotype and enhancing T cell activation. Specific microbial strains, such as Lactobacillus plantarum and Bifidobacterium, also stimulate NK cell activation, reinforcing antitumor immunity. Systemically, these microbiota-driven immune responses extend beyond the gut, increasing CTL infiltration into distant tumor sites, particularly within the tumor microenvironment (TME). Notably, Bifidobacterium, Clostridiales, and certain microbial metabolites enhance CD8 + T cell infiltration into tumor tissues, strengthening the immune response against cancer. Furthermore, gut microbiota-derived antigens share similar epitopes with tumor-associated antigens, promoting cross-reactivity and amplifying tumor-targeting immune responses. Conversely, some microbial metabolites may inhibit T cell recognition of tumor epitopes, potentially dampening anti-tumor immunity.

Shaping innate and adaptive immunity

Growing evidence indicates that gut microbiota plays a crucial role in regulating innate immunity by influencing immune signaling and maintaining gut barrier integrity. The microbiota shapes the development and function of key innate immune cells, including DCs and macrophages. Disruptions in microbial balance weaken the intestinal mucosal barrier, allowing microbial products such as lipopolysaccharides (LPS), peptidoglycan, and flagellin to enter the bloodstream. These microbial components activate pattern recognition receptors (PRRs), such as TLRs and NLRs, triggering proinflammatory cytokine production, DC maturation, and NK cell activation, all of which contribute to immune responses and inflammation 121 . Additionally, specific gut bacteria activate PRRs within gut-associated lymphoid tissue (GALT) and mesenteric lymph nodes, further stimulating DCs and enhancing immune function 122 . For example, Bifidobacterium bifidum and Bifidobacterium fragilis promote innate immunity by interacting with DCs and macrophages through their metabolites and stimulating the release of cytokines such as IL-12 and TNF-α 92 , 93 , 123 . Gut microbiota also influence innate immune signaling through NLRs. Studies suggest that commensal bacteria help regulate intestinal inflammation by interacting with these receptors 124 – 126 . In addition, lactobacillus plantarum can enhance the expression of natural cytotoxicity receptors (NCRs), activating NK cells and reinforcing innate immunity 127 . Furthermore, the microbiota plays a role in shaping the phenotype and function of innate lymphoid cells (ILCs), particularly ILC3s, further underscoring its importance in immune regulation 128 . For instance, Gut microbiota metabolites can directly modulate ILC3 functions, influencing cytokine production, tissue repair, and inflammation regulation 129 . These interactions subsequently alter the immune microenvironment, which can enhance or impair responses to cancer immunotherapy. Recent studies highlight that microbial-derived aryl hydrocarbon receptor (AhR) ligands enhance ILC3 functionality, promoting anti-tumor immunity and improving immunotherapeutic outcomes 130 .

Beyond innate immunity, gut microbiota contributes to the development of adaptive immune responses, particularly through molecular mimicry and thus stimulation of T cell activation and differentiation, which in turn influence systemic immune homeostasis 131 – 133 . Studies suggest that gut microbes regulate CD4 + T cell subtypes, including Th1, Th2, Th17, and regulatory T cell (Treg) 134 – 136 . Germ-free (GF) mice, for instance, exhibit an imbalance skewed toward a Th2-dominant response 137 . Certain bacterial species, such as Bacteroides fragilis, produce polysaccharide A (PSA), which engage TLR 2/1 heterodimers and Dectin-1, triggering downstream phosphoinositide 3-kinase signaling 138 . This cascade leads to the production of the immunomodulatory cytokine IL-10 by CD4+ Tregs, contributing to immune homeostasis. The gut microbiota also influences intestinal CD8 + T cell function, which extends to the regulation of peripheral immune cells 139 – 142 . Moreover, the gut microbiota has been shown to play a dual role in cancer progression by mediating B cell responses and thus modulating immune responses. On the one hand, B-cell responses that are indirectly induced by specific microbiota (e.g., Bifidobacterium bifidum, Ackermannia spp.) through activation of DC and CD8 + T cells may promote antitumor immunity through the production of tumor-reactive antibodies, the enhancement of antigen presentation, and the promotion of cytotoxic T-cell responses 143 , 144 . Conversely, under certain conditions, certain intestinal flora (e.g., Mycobacterium spp.) may attenuate T-cell-mediated antitumor responses by inducing regulatory B-cell differentiation and secreting immunosuppressive factors such as IL-10 and TGF-β 143 . The specific microbial communities and their metabolites play a pivotal role in determining whether B cells exert tumor-promoting or tumor-suppressive effects.

Disruptions in microbiota-T cell interactions can create a proinflammatory environment within and beyond the gastrointestinal tract, including the TME. These insights highlight the intricate crosstalk between the gut microbiota and host immunity, offering potential therapeutic avenues to enhance immunotherapy efficacy.

Harnessing metabolites for the regulation of anti-tumor immunity

Gut microbiota influence both systemic and tumor-specific immune responses through their metabolites—small molecules that diffuse from the gut and modulate the immune system 145 . These microbial metabolites can be broadly categorized based on their origin and synthesis: (1) metabolites derived from dietary components, such as SCFAs, tryptophan metabolites, and inosine; (2) host-produced metabolites modified by gut microbiota, such as secondary bile acids; and (3) metabolites synthesized directly by gut microbiota, including branched-chain amino acids (BCAAs) and vitamins 146 .

SCFAs, such as butyrate and propionate, play a key role in immune regulation. Bacteroidetes, Lachnospiraceae, and Roseburia produce propionic acid via the succinate or acrylic acid pathways, while Firmicutes species, including Ruminococcus and Clostridium, generate butyric acid 147 , 148 . These SCFAs are absorbed in the colon and influence T cell differentiation through G-protein-coupled receptor signaling and histone deacetylase inhibition 149 , 150 . Similarly, tryptophan metabolism by gut microbiota yields various bioactive compounds, such as indoles, 5-hydroxytryptamine, and kynurenine, which exert bidirectional effects on immune responses 151 . For example, Lactobacillus reuteri metabolizes tryptophan in the TME to produce indole-3-aldehydes, which enhance CD8+ T cell activity and inhibit melanoma growth via AhR signaling 152 . However, in pancreatic ductal adenocarcinoma (PDAC) models, Lactobacillus reuteri-derived tryptophan metabolites activate TAMs, promoting an immunosuppressive phenotype 153 . These findings highlight the need for tumor-specific intervention strategies. Other microbial metabolites also modulate immune responses. Inosine, a purine metabolite produced by Akkermansia muciniphila and Bifidobacterium longum, enhances antitumor immunity by inhibiting UBA6 expression in tumor cells, thereby increasing tumor immunogenicity 154 . Additionally, inosine interacts with adenosine 2A receptors on T lymphocytes, leading to IL-12 receptor β2 activation and IFN-γ upregulation, further strengthening immune responses 155 .

Gut microbiota-derived lipid metabolites, particularly sphingolipids such as ceramides and sphingosine-1-phosphate (S1P), also significantly modulate immune responses and influence cancer immunotherapy efficacy 156 – 158 . Sphingolipids not only serve as structural components of cellular membranes but also act as signaling molecules that regulate cell behavior and immune cell communication. Specific gut microbes, including Bacteroidetes, produce sphingolipids that shape host immune responses 157 , 159 . These microbiota-derived sphingolipids can either enhance or impair the efficacy of immunotherapies by modulating immune cell trafficking, proliferation, and activation. For instance, S1P has been shown to regulate lymphocyte egress from lymphoid tissues, influencing their availability at tumor sites, thus directly impacting immunotherapy outcomes 160 . The immunomodulatory roles of these lipid metabolites underscore the importance of exploring microbial lipid metabolism further to develop targeted strategies enhancing the effectiveness of cancer immunotherapies.

Bile acids, primarily converted by gut microbiota in the cecum and colon, also influence immune function. Species within Firmicutes, particularly Clostridium, convert primary bile acids into secondary bile acids such as lithocholic acid (LCA) and deoxycholic acid (DCA) 161 . These metabolites regulate T cell differentiation and macrophage polarization, with secondary bile acids notably suppressing Th17 cell function 162 , 163 . However, their effects on tumor immunity are complex. For example, secondary bile acids from Clostridium scindens impair the tumor-suppressive function of NKT cells 109 . In contrast, LCA inhibits breast cancer cell growth by activating TGR5 and constitutive androstane receptors, leading to oxidative stress, suppression of epithelial-mesenchymal transition (EMT), and reduced angiogenesis and metastasis 164 . Gut microbiota also produce BCAAs and vitamins that influence anti-tumor immune response. Bacteria degrade proteins and unabsorbed amino acids to synthesize BCAAs such as leucine, isoleucine, and valine, which promote effector T cell activation and proliferation through mTORC1 signaling 165 . Meanwhile, Firmicutes (such as Lactobacillus and Enterococcus) and Bacteroides synthesize B vitamins. Bacteroides fragilis, Prevotella, and Ruminococcus lactis produce vitamin B3, which binds to GPR109A receptors in myeloid cells, inhibiting NF-κB signaling, reducing immunosuppressive myeloid cell polarization and enhancing CD8 + T cell cytotoxicity 166 , 167 . Likewise, vitamin B6, synthesized by Lactobacillus acidophilus and Bifidobacterium bifidum, boosts T lymphocyte proliferation and promotes antitumor immunity by stimulating T cell activity 168 , 169 .

These findings underscore the critical role of microbial metabolites in shaping antitumor immune responses. However, their bidirectional effects and individual variability present challenges in therapeutic applications. To maximize their potential, future research must integrate multi-omics data and develop personalized strategies to optimize tumor immunotherapy with minimal toxicity.

Synergizing ICI to enhance antitumor efficacy and managing risks

As previously mentioned, the gut microbiota has the capacity to augment the efficacy of immunotherapy by modulating host immunity. However, several studies have demonstrated that the gut microbiota can also interact with immunotherapy to further enhance its efficacy. Vétizou et al. found that Bacteroides thetaiotaomicron and Bacteroides fragilis stimulate TLR4- and IL-12- dependent T helper 1 (Th1) responses, enhancing the effects of CTLA-4 blockade 94 . Other studies have shown that Firmicutes and Actinobacteria activate mucosa-associated innate T cells and CD56 + CD8+ T cells in peripheral blood, increasing the expression of human leukocyte antigen (HLA) class II genes, CD74, and granzyme K (GZMK) in CD8+ T cells at tumor sites, thereby improving anti-PD-1 responses 55 . Certain bacterial species also facilitate immune cell infiltration into tumors, further amplifying the effects of immunotherapy. Enterococcus hirae migrates from the small intestine to secondary lymphoid organs, increasing the intratumoral CD8 + T/Treg ratio, while Bacteroides intestinihominis accumulates in the colon and stimulates IFN-γ-producing γδ T cells, improving cyclophosphamide efficacy in advanced lung and ovarian cancer patients 115 , 170 . Similarly, Akkermansia and high-fiber diets have been shown to induce tumor-infiltrating NK cell-DC interactions through stimulator of interferon genes (STING) signaling, leading to type I interferon (IFN-I) production and enhanced ICI efficacy 171 . Additionally, Bifidobacterium preferentially accumulates in tumors and promotes CD47-based immunotherapy in a STING- and interferon-dependent manner 172 . Beyond direct immune modulation, the commensal microbiota may also activate tumor antigen-specific T cell responses by modulating the immunogenicity of tumor cells. Microbiota can enhance ICI efficacy by providing tumor cross-antigens that stimulate tumor-specific T cell responses 131 , 173 , 174 . Fluckiger et al. found that a tail-length tapering protein (TMP) from an Enterococcus phage closely resembles the proteasomal subunit β-4, triggering TMP-specific CD8+ T cell responses during cyclophosphamide or anti-PD-1 therapy 173 . Similarly, Bessell’s team identified an antigenic epitope (SVYRYYGL) in Bifidobacterium breve that mimics the tumor epitope (SIYRYYGL), enabling cross-reactive T cell responses that suppress tumor growth 174 . Moreover, bacterial-specific peptides have been identified in HLA molecules from glioblastoma tissues and tumor cell lines, suggesting a direct link between gut microbiota and tumor antigen presentation 175 .

While gut microbiota enhance immunotherapy, they also play a dual role in modulating immunotherapy-related toxic responses, particularly immune-associated adverse events (irAEs), either by promoting immune homeostasis and treatment tolerance or by exacerbating adverse effects through immune dysregulation (Fig. 3 ). These toxicities vary by therapy type—anti-CTLA-4 therapy is often linked to colitis and pituitary inflammation, anti-PD-1 therapy to thyroid dysfunction and pneumonitis, and CAR-T therapy to cytokine release syndrome (CRS) and neurotoxicity 176 – 178 . A key mechanism underlying immunotherapy-related toxicity is intestinal barrier disruption. Studies show that SCFA-rich diets can significantly reduce gastrointestinal toxicity induced by immunotherapy 179 , 180 . Specific microbial taxa, such as Akkermansia muciniphila and members of the Ruminococcaceae family, have been associated with high-fiber and omega-3-rich diets, promoting both optimal antitumor immune responses and reduced irAEs by supporting mucus turnover and epithelial integrity 64 . Certain bacterial populations also confer resistance to irAEs. For instance, increased Bacteroidetes abundance has been linked to reduced colitis risk in anti-CTLA-4 therapy, and Bacteroides vulgatus and Bacteroides dorei were found to correlate negatively with irAE development in metastatic melanoma patients receiving anti-CTLA-4 and anti-PD-1 treatment 44 , 181 . Furthermore, FMT from healthy donors has been shown to restore microbial diversity, increase Treg proportions in colonic mucosa, and mitigate ICI-induced colitis 182 . Fig. 3 Bidirectional regulation of immunotherapeutic toxicity by gut microbiota. LPS, lipopolysaccharide; SCFA, short chain fatty acids; FMT, fecal microbiota transplantation. With respect to the amplification of immunotherapy toxicity, the presence of certain bacterial species, including Lactobacillus intestinalis, Streptococcus, and E. faecalis, along with other Firmicutes, disrupt the intestinal barrier, leading to elevated levels of LPS and promotion of Th17 cell activation, which in turn, promotes an increase in interleukin-17 (IL-17) secretion and inflammatory response. Conversely, microbiota exemplified by Akkermansia muciniphila, Lactobacillus, Bifidobacterium fragilis, and Bifidobacterium bifidum, as well as FMT from healthy donors, which collectively enhanced Treg activity, promoted SCFA production, and upregulated anti-inflammatory cytokines such as IL-10 and TGF-β, thereby reducing immunotherapy toxicity.

Conversely, gut microbiota imbalances can amplify immunotherapy toxicity by fostering pro-inflammatory conditions. For example, a high abundance of Bacteroides intestinalis has been associated with colitis and upregulation of mucosal IL-1β in melanoma patients treated with anti-CTLA-4 and anti-PD-1 therapy 56 . Additionally, studies in mice have shown that antibiotic treatment can reduce colitis, CRS, and liver injury caused by immunoagonist therapy, suggesting a microbiota-driven mechanism 183 . However, antibiotic use has also been linked to increased neurotoxicity in patients receiving CD19-targeted CAR-T therapy 71 . Interestingly, baseline gut microbiota composition may predict both treatment efficacy and toxicity. In metastatic melanoma patients treated with anti-CTLA-4, an abundance of Faecalibacterium and other Firmicutes was associated with improved treatment responses but higher irAEs, whereas Bacteroidetes correlated with poorer responses and lower irAE incidence—an effect termed the “efficacy-toxicity coupling effect” 184 .

These findings underscore the complex and individualized nature of microbiota-mediated immune regulation in immunotherapy. However, the mechanisms of the gut microbiota are complex and individualized, and further studies are needed to elucidate the precise pathways of the gut microbiota before translating its regulatory role into new strategies in clinical treatment.

The intratumoral microbiome: a critical regulator of TME and immunotherapy responses

The TME constitutes a sophisticated ecosystem that includes tumor cells, stromal cells, immune cells, and an intricate molecular and physical landscape. A critical yet often overlooked component of this ecosystem is the tumor-associated microbiota, consisting of bacteria, fungi, archaea, and viruses, which are either intrinsically present at the tumor site or translocated into tumors via various physiological routes 152 , 185 , 186 . Recent research has underscored the pivotal roles these microbial communities play in tumorigenesis, progression, metastasis, and response to cancer therapies 187 .

The composition and diversity of the intratumoral microbiota are variable across cancer types, reflecting distinct environmental niches and tumor-specific physiological conditions. For instance, breast cancer tissues exhibit richer microbial diversity compared to other cancers, predominantly harboring Proteobacteria and Firmicutes 188 . In gastrointestinal cancers, a notable enrichment of Fusobacterium nucleatum (Fn) has been documented 189 – 192 . In gastric cancer, Fn recruits tumor-associated neutrophils via IL17/NF-κB signaling, driving their polarization toward immunosuppressive phenotypes and increasing PD-L1 expression. Paradoxically, Fn-infected tumors exhibit increased sensitivity to anti-PD-L1 therapy, indicating dual roles in immune modulation 189 . Similarly, in CRC, Fn secretes the Fap2 protein, which interacts with TIGIT receptors on NK cells, thereby inhibiting their activity, recruiting myeloid-derived suppressor cells (MDSCs), and enhancing tumor cell proliferation while impairing antitumor immunity 190 . Moreover, Fusobacterium nucleatum has been found to colonize hepatic metastases via hematogenous dissemination, subsequently promoting tumor cell invasiveness through activation of the TLR4/MyD88 signaling axis 191 . In NSCLC, butyrate-producing bacteria, notably Roseburia, correlate with disease recurrence and metastasis. Circulating microbial DNA signatures enriched with butyrate producers have also emerged as predictive biomarkers for recurrence, underscoring the clinical relevance of microbial metabolites 192 .

Microbial influence on tumor progression also extends to other cancer types. In squamous cell carcinoma, Staphylococcus species release enterotoxin B, which enhances the expression of CD4 + STAT5 and HDAC-1 in T cells, subsequently increasing IL-9 secretion and promoting apoptosis of carcinoma cells 193 . Additionally, microbial metabolites significantly impact tumor development through mechanisms such as induction of DNA damage and activation of oncogenic pathways 194 . Escherichia coli, for example, produces colibactin, leading to DNA methylation changes and double-strand DNA breaks. Similarly, Bacteroides fragilis generates reactive oxygen species (ROS), thereby inducing genomic instability and facilitating tumorigenesis 195 , 196 .

The intratumor microbiota is not only affected by the dynamics of the TME, but also acts as a feedback regulator of its morphology and function. Hypoxia, low pH, and metabolic stress in the TME may be more favorable for the growth of both parthenogenetic and purely anaerobic bacteria 197 . Bifidobacterium, for example, migrates to colonize and enrich CRC tumors 198 . The microbiota, in turn, affects the TME through metabolic and immune interactions. Numerous studies have demonstrated that specific gut microbiota and their metabolites influence the TME by promoting the formation and maturation of tertiary lymphoid structures (TLS). TLS serve as critical hubs for local immune activation, facilitating the recruitment, organization, and activation of immune cells, notably antigen-presenting cells, T cells, and B cells, thus coordinating robust anti-tumor immunity. For example, in CRC mouse models, the gut commensal bacterium H. hepaticus has been shown to drive TLS formation by inducing CD4+ T cell differentiation into follicular helper T (Tfh) cells, thereby enhancing immune cell infiltration within the TME 199 . Additionally, microbial metabolites such as SCFAs and trimethylamine N-oxide can reshape the TME to support TLS maturation through activation of the STING signaling pathway and enhancement of T and NK cell activity 200 . Furthermore, other microbial-derived metabolites—including indole derivatives, hydrogen sulfide, and bile acids—modulate tumor cell metabolism and immune homeostasis 201 . The dynamic evolution of the gut microbiome is intimately associated with mechanisms of immune escape in tumors. Specific Clostridium spp. produce metabolites that induce the differentiation of Tregs while inhibiting the establishment of immunosuppression in the TME 202 . Moreover, D-Lactate produced by Lactobacillus is capable of converting M2-type TAMs to M1-type, thereby remodeling the TME and enhancing anti-tumor immune responses 203 .

Given these insights, targeting tumor-associated microbiota and their metabolites emerges as a promising therapeutic strategy. Synthetic microbiome interventions, inhibitors against specific tumor-associated bacteria, or microbiome-based metabolite modulation could effectively disrupt oncogenic microbial interactions, thereby enhancing immune responsiveness and treatment efficacy. Future research should thus prioritize comprehensive characterization of the intratumoral microbiome across diverse cancer types, unraveling the precise molecular mechanisms underlying microbial-tumor-immune interactions. This approach holds significant potential for optimizing personalized cancer immunotherapy strategies, ultimately improving patient outcomes across multiple malignancies.

Strategies for gut microbiota intervention combined with immunotherapy

The composition and diversity of the gut microbiota are closely linked to the efficacy of cancer therapies. Beyond merely understanding these associations, researchers are now exploring ways to modulate the microbiota to enhance immunotherapy effectiveness and reduce toxicity. Strategies for microbiota-targeted interventions combined with immunotherapy include antibiotics, FMT, probiotics, dietary and prebiotic-based approaches, and engineered microbiota therapies (Fig. 4 ). A multitude of pertinent clinical trials are currently ongoing, and a comprehensive review of studies pertaining to these therapeutic strategies from recent years is provided below. Fig. 4 Therapeutic strategies combining gut microbial interventions with immunotherapy. FMT, fecal microbiota transplantation. Gut microbiota modulation through different approaches, including antibiotics, FMT, probiotics, diet and prebiotics, and other strategies, has been shown to influence immunotherapy outcomes. Selective antibiotics, such as vancomycin and tigecycline, can be beneficial, whereas broad-spectrum antibiotics may negatively impact treatment response. FMT, administered via oral capsules, colonoscopy, or gastroscopy, facilitates the transfer of beneficial gut microbiota from immunotherapy-responsive donors to patients. The use of probiotics, including Lactobacillus, Bifidobacterium, Clostridium butyricum, and Akkermansia, supports a favorable gut microbial composition. Diet and prebiotics, such as inulin gel, pectin, high-fiber diets, fasting-mimicking diets, and ketogenic diets, contribute to microbiota modulation and immune system support. Additionally, other strategies, including engineered microorganisms, microbial peptides, and microbial metabolites, represent emerging therapeutic approaches. These interventions collectively contribute to optimizing gut microbiota composition, thereby promoting immune responses and enhancing immunotherapy efficacy.

Antibiotics

The utilization of antibiotics in the management of patients with malignant tumors is predominantly driven by postoperative prophylactic infections, treatment-related infections, and the management of comorbidities. However, these interventions inevitably alter the gut microbiota, potentially affecting immunotherapy outcomes 204 – 206 . Preclinical and clinical studies suggest that antibiotic use, particularly broad-spectrum antibiotics, may impair ICI efficacy (Table 2 ) 95 , 207 – 228 . In mouse models of NSCLC and melanoma, antibiotics such as vancomycin, ampicillin, metronidazole, and neomycin disrupted IL-17-producing γδT17 cells, promoting tumor metastasis 229 . Clinical studies have similarly reported reduced progression-free survival (PFS) and overall survival (OS) in patients with advanced RCC and NSCLC who received antibiotics prior to ICI therapy 230 . The results of a retrospective analysis and two clinical studies related to ICI for NSCLC showed that both antibiotics and another microbiologically modifiable proton pump inhibitor significantly shortened PFS and OS in patients treated with atalizumab 231 . These findings suggest a pivotal role for the antibiotic-influenced gut microbiota in ICI treatment. Table 2 Some Clinical studies of Antibiotic-modulated immunotherapy Cancer type Patients (n) Antibiotics Intervention Immunotherapy Ref. Melanoma; NSCLC; etc. 196 β-Lactam; quinolone; macrolides; sulfa; etc. αPD-1/αPD-L1 mAb; 95 Melanoma; NSCLC; lung cancer; urothelial carcinoma; RCC; sarcoma 2740 Antibiotics αPD-1/αPD-L1 mAb; 207 Melanoma; lung cancer; RCC; UC; etc. 2889 Antibiotics αPD-1/PD-L1 mAb, αCTLA-4 mAb, or combination treatment 208 Melanoma; NSCLC; lung cancer; RCC; etc. 5565 β-Lactam; quinolone; vancomycin; daptomycin; etc. αPD-1/PD-L1 mAb, αCTLA-4 mAb, or combination treatment 209 Advanced melanoma 1585 Systemic antibiotic αCTLA-4 mAb 210 NSCLC; RCC; AML 338 Piperacillin; clindamycin; metronidazole. meropenem; vancomycin; furantoin; rifampin. rifaximin; tobramycin ICI; chemotherapy 211 mRCC 4290 β-Lactam; fluoroquinolone; macrolides; tetracyclines; etc. αPD-1/PD-L1 mAb; mTOR inhibitors; IFN-α; VEGF-TT 212 HCC 450 β-Lactams; quinolones; etc. αPD-1/PD-L1 mAb, αCTLA-4 mAb, or combination treatment 213 Melanoma; NSCLC; blood cancer; renal cancer; etc. 635 β-Lactam, sulfa, quinolones, macrolides aminoglycosides; tetracycline αPD-1/PD-L1 mAb, αCTLA-4 mAb, or combination treatment 214 Melanoma; NSCLC; RCC; etc. 12,492 β-Lactam; fluoroquinolone; penicillins; carbapenems; etc. αPD-1/PD-L1 mAb, αCTLA-4 mAb, or combination treatment 215 Melanoma 568 Cephalosporins; penicillins; fluoroquinolone αPD-1 mAb; αCTLA-4 mAb; combined 216 Lung cancer; etc. 767 Antibiotics αPD-1/αPD-L1 mAb; 217 NSCLC 256 Antibiotics αPD-1/PD-L1 mAb, αCTLA-4 mAb 218 B cell lymphoma; leukemia 228 Piperacillin/tazobactam, meropenem and imipenem/cilastatin (P-I-M) Anti-CD19 CAR-T 71 Lung cancer; esophagus cancer; gastrointestinal cancer; etc. 168 Antibiotics αPD-1 mAb 219 Melanoma 2605 Amoxicillin; amoxicillin; pristinamycin; ofloxacin αPD-1 mAb 220 HNSCC 3651 Extended spectrum penicillins; cephalosporins; quinolones αPD-1 mAb 221 HCC 4098 Antibiotics αPD-1/PD-L1 mAb, αCTLA-4 mAb, or combination treatment 222 Leukaemia; lymphoma; melanoma; myeloma; etc. 111,260 Amoxicillin; flucloxacillin; trimethoprim; erythromycin; etc. ICI; chemotherapy 205 HER2-negative BC 66 Fluoroquinolones; cephalosporins αPD-1 mAb 223 Melanoma 14 Vancomycin αPD-1mAb 224 NSCLC 2028 Cephalosporins; sulfonamides; quinolones αPD-1/αPD-L1 mAb, or combined chemotherapy 225 Large B-cell lymphoma 422 Broad-spectrum ABX Anti-CD19 CAR-T 226 ES-SCLC 198 Systemic antibiotic Atezolizumab/chemotherapy 227 SCC 104 Beta lactams; cyclins; fluoroquinolones; aminosides; etc. αPD-1mAb 228 NSCLC non-small-cell lung cancer, RCC renal cell carcinoma, UC urothelial carcinoma, AML acute myeloid leukemia, HNSCC head and neck squamous cell carcinoma, HCC hepatocellular carcinoma, ES-SCLC extensive-stage small cell lung cancer, SCC squamous cell carcinoma, ABX antibiotic cocktail regimen.

The impact of antibiotics on tumor immunotherapy is also related to the duration of patient exposure to antibiotics. A multicenter prospective study reported that antibiotic treatment given prior to, but not at the time of, ICI treatment were associated with poorer response and lower OS 118 . Conversely, another study suggested that antibiotic use within 30 days before or after ICI initiation correlated with improved benefit from immunotherapy 213 . The divergent outcomes observed in the two studies may be attributable to factors such as the timing of antibiotic administration, the specific nature of the tumor, and individual variations. A meta-analysis further highlighted the impact of antibiotic timing, showing that patients who avoided antibiotics within 42 days before ICI therapy had significantly longer OS than those who received antibiotics within 60 days prior to treatment, which is consistent with previous findings, as the microbiota returned to near-baseline levels within 42 days after administration of an antibiotic cocktail regimen (ABX) for 4 days to healthy adults 208 , 232 . The aforementioned studies underscore the pivotal role of the temporal aspect of antibiotic administration in the context of immunotherapy. Additionally, broad-spectrum antibiotics appear to have a more detrimental impact on OS compared to narrow-spectrum antibiotics 226 , 233 .

Despite concerns about their negative impact on immunotherapy, certain antibiotics may enhance treatment efficacy when used selectively. Vancomycin, which targets gram-positive bacteria such as Clostridium difficile, has been shown to promote NKT cell migration and IFN-γ production, thereby inhibiting primary and metastatic HCC growth in mice 109 , 234 . A clinical trial ( NCT03785210 ) is currently evaluating the efficacy of vancomycin in combination with ICIs for HCC treatment. Antibiotics may also counteract tumor-associated microbial activities that impair therapy. For example, some Clostridium species synthesize androgens, reducing the effectiveness of androgen deprivation therapy (ADT) in prostate cancer 235 . Vancomycin-containing antibiotic regimens may enhance ADT efficacy by eliminating these bacteria 236 . Similarly, tigecycline has demonstrated synergistic effects with B-cell lymphoma-2 inhibitors, suggesting potential therapeutic applications in diffuse large B-cell lymphoma 237 . Beyond systemic effects, localized antibiotic interventions may be particularly beneficial in tumors with a high microbial burden. The pancreas, due to its anatomical connection with the gut, harbors a substantial microbial load linked to pancreatic cancer progression and immunosuppression 238 , 239 . ABX has been shown to disrupt these microbial communities, inhibits pancreatic ductal adenocarcinoma invasion, and promotes ICI outcome by increasing the differentiation of M1 macrophages and Th1 CD4 + T cells, activating CD8 + T cells, and upregulating the expression of PD-1 on effector T cells 240 . Additionally, ABX can reduce bacterial translocation to the liver and intestine, thereby inhibiting CRC metastasis 241 .

While antibiotics offer potential benefits in modulating tumor-associated microbiota, their application in cancer treatment must be carefully tailored. Factors such as the patient’s immune status, tumor genetics, TME, and antibiotic resistance should be considered. Therefore, treatment regimens should be tailored to the specific condition of the patient and can be based on pre-treatment sequencing of the gut microbiome and targeted formulation design approaches to enhance treatment efficacy while reducing disruption of the gut microbiota by broad-spectrum antibiotics.

FMT

FMT refers to the reconstitution of a new intestinal flora by transplanting functional flora from healthy human feces into a patient’s gastrointestinal tract, either orally or via colonoscopy or gastroscopy. Originally developed to treat refractory Clostridium difficile infections, FMT has since been explored for other gastrointestinal disorders such as Crohn’s disease and ulcerative colitis 242 – 244 . Its potential in oncology has emerged from preclinical studies demonstrating that germ-free mice receiving fecal transplants from immunotherapy-responsive patients exhibit stronger anti-tumor immune responses compared to those receiving transplants from non-responders 46 , 94 .

Currently, clinical trials investigating FMT in cancer immunotherapy are in early stages (Table 3 ) 244 – 275 . Two independent trials ( NCT03353402 and NCT03341143 ) first demonstrated that FMT could overcome resistance to ICI therapy in metastatic melanoma 26 , 55 . In NCT03353402 , 10 patients with PD-1–refractory melanoma underwent FMT followed by renewed anti-PD-1 therapy, resulting in tumor reduction in three patients, including two partial responses (PRs) and one complete response (CR) 26 . Similarly, NCT03341143 assessed FMT combined with pembrolizumab in 15 patients, yielding two PRs, one overall response (OR), and three cases of stable disease (SD) lasting over a year 55 . These studies also highlighted favorable immune changes, including increased CD8 + T-cell activation and reduced IL-8–expressing myeloid cells. Microbiome analysis revealed enrichment of beneficial bacteria (Bifidobacterium longum, Lachnospiraceae, Ruminococcaceae) and a decline in potentially detrimental species such as Bacteroides. Additionally, microbial diversity changes correlated with increased levels of primary and secondary bile acids and benzoic acid metabolites. A subsequent FMT study ( NCT03772899 ) differed from the two previous studies. The present study was distinctive in that its FMT donor was from a healthy individual. Although its conclusions are subject to further validation due to the trial’s small sample size and lack of a control group, the preliminary results suggest that the use of a healthy donor is also a safe alternative. Concomitantly, this prompts further inquiry into the optimal FMT donor: a cancer survivor with heightened sensitivity to immunotherapy, or a non-malignant individual devoid of a medical history 74 . Table 3 Clinical trials of FMT interventions on immunotherapy Phase (Trial ID) Patients (n) Cancer type Immunotherapy treatment Primary outcomes measures Ref. II ( NCT06218602 ) 40 Lymphoma anti-CD19 CAR-T Safety, AEs 244 I ( NCT03353402 ) 40 Melanoma αPD-1 mAb AEs, proper implant engraftment 245 I ( NCT03772899 ) 20 Melanoma αPD-1 mAb Safety 246 I/II ( NCT05251389 ) 24 Melanoma αPD-1 mAb Efficacy 247 II ( NCT03341143 ) 18 Melanoma αPD-1 mAb ORR 248 NA ( NCT04577729 ) 60 Melanoma ICI PFS 249 II ( NCT06623461 ) 128 Melanoma ICI and LND101 PFS 250 I/II ( NCT04521075 ) 50 Melanoma, NSCLC αPD-1 mAb AEs, ORR 251 II ( NCT04951583 ) 70 Melanoma, NSCLC αPD-1 mAb or αPD-1 mAb plus αCTLA-4 mAb ORR 252 I ( NCT05008861 ) 20 NSCLC αPD-1 mAb and chemotherapy AEs, ORR 253 II ( NCT06403111 ) 62 NSCLC αPD-1 mAb and chemotherapy 12 month-PFS 254 II ( NCT05502913 ) 80 Lung Cancer (Chemo-) immunotherapy PFS 255 NA ( NCT04924374 ) 20 NSCLC αPD-1 mAb Safety, Response 256 I ( NCT04056026 ) 1 Mesothelioma αPD-1 mAb PFS 257 III ( NCT06486220 ) 96 NPC αPD-1 mAb and chemotherapy PFS 258 II ( NCT05750030 ) 12 HCC αPD-L1 mAb plus VEGF-α mAb Safety, AEs 259 II ( NCT05690048 ) 48 HCC αPD-L1 mAb plus VEGF-α mAb Differential tumoral CD8 T-cell infiltration, AEs 260 II ( NCT06405113 ) 198 Gastric Cancer αPD-1 mAb plus SOX 2-year ORR 261 I ( NCT04130763 ) 10 Gastrointestinal cancer αPD-1 mAb ORR, Abnormal vital signs, AEs 262 I ( NCT04038619 ) 40 Gastrointestinal cancer ICI AEs, Remission of diarrhoea/ colitis 263 I ( NCT04729322 ) 15 CRC αPD-1 mAb ORR 264 II ( NCT05279677 ) 30 CRC αPD-1 mAb and TKI ORR 265 I ( NCT04163289 ) 20 Renal cancer αPD-1 mAb or αCTLA-4 mAb Immune-related colitis 266 I ( NCT04038619 ) 40 RCC ICI AEs, ICI-related diarrhea/colitis 267 I/II ( NCT04758507 ) 50 RCC ICI Incidence of tumor progression 268 II ( NCT04116775 ) 32 Prostate cancer αPD-1 mAb and hormone therapy Efficacy 269 I ( NCT04883762 ) 4 Solid tumors ICI AEs 270 I/II ( NCT04521075 ) 42 Solid tumors αPD-1 mAb AEs, ORR 271 II ( NCT05286294 ) 20 Solid tumors ICI Safety, ORR 272 I/II ( NCT03819296 ) 800 Solid tumors Infliximab/Vedolizumab AEs, ICI-related colitis 273 NA (ChiCTR2100042292) 30 Solid tumors Immunotherapy Change in microbiota, Immune status, AEs 274 NA ( NCT04264975 ) 60 Solid tumors Immunotherapy ORR 254 NA ( NCT05273255 ) 18 Malignancies Immunotherapy Change in intestinal microbiome community 275 NSCLC non-small-cell lung cancer, ICI immune checkpoint inhibitor, ORR objective response rate, PFS progression-free survival, AEs adverse events, NPC nasopharyngeal carcinoma, HCC hepatocellular carcinoma, CRC colorectal cancer, SOX oxaliplatin and capecitabine, RCC renal cell carcinoma.

Beyond tumor response, FMT is also being explored for managing irAEs, particularly in reducing steroid-refractory colitis. Trials such as NCT03819296 , NCT04038619 , NCT04721041 , and NCT04163289 are assessing its potential to mitigate irAEs. Early studies suggest FMT is effective in treating steroid-resistant gastrointestinal graft-versus-host disease (GvHD) following hematopoietic stem cell transplantation (HSCT), with patients showing significant clinical remission 276 , 277 . Similarly, in ICI-induced colitis, case reports and small trials indicate that FMT can restore gut homeostasis, with notable increases in beneficial microbes such as Akkermansia, Blautia, and Bifidobacterium 182 . A study by Halsey et al. reported that 92% of 12 patients with refractory immune-mediated colitis achieved clinical remission post-FMT, accompanied by increased gut microbial diversity and enrichment of Collinsella and Bifidobacterium 278 . These findings, supported by numerous ongoing and completed trials, reinforce the therapeutic potential of FMT in malignancies 279 – 282 . Despite these promising outcomes, concerns remain regarding the long-term safety of FMT. In 2019, two patients developed Escherichia coli bacteremia, with one fatality, following FMT from the same donor 283 . This finding prompted the Food and Drug Administration (FDA) to issue a safety warning regarding the risk of infection with FMT therapy. A retrospective study further revealed that 9% of screened donors carried multidrug-resistant organisms, highlighting the need for stringent donor screening protocols, particularly for immunocompromised patients 284 .

However, not all PD-1–refractory patients respond to renewed therapy after FMT, likely due to factors such as immunosuppression, donor-recipient microbiota incompatibility, or suboptimal FMT delivery methods. Additionally, there are many off-target microbiota components in donor feces that are transplanted into recipients that have unknown effects. Future research should focus on refining microbiota transfer protocols, identifying optimal donor-recipient pairings, and integrating FMT with complementary approaches to enhance antitumor efficacy.

Probiotics

The concept of probiotics, first introduced by Metchnikoff, refers to live microorganisms that confer health benefits when administered in sufficient quantities 285 , 286 . Preclinical studies indicate that supplementing specific gut microbes, such as Lactobacillus, Bifidobacterium, Enterococcus, Faecalibacterium, and Ruminococcaceae, can enhance tumor immunotherapy 287 – 291 . For instance, Bifidobacterium pseudolongum produces inosine, which activates the T cell adenosine A2A signaling pathway, improving immunotherapeutic efficacy 176 . Similarly, Bifidobacterium bifidum K57 supplementation has been shown to boost the immune response against the TME by enhancing CD4+ and CD8 + T cell activation and increasing IFN-γ and IL-2 secretion, thereby synergizing with anti-PD-1 therapy to reduce tumor burden 290 .

Advancements in NGS have identified Akkermansia as another probiotic that promotes immunotherapy 292 , 293 . In Peyer’s patches, Akkermansia induces an increase in Tfh cells, while its outer membrane protein, Amuc, triggers adaptive immune responses by activating the TLR2 signaling pathway and decreasing immunosuppressive Treg cell levels 294 , 295 . In addition, commensal bacterial strains contribute to immunotherapy by maintaining gut homeostasis. Tanoue et al. isolated 11 bacterial strains from healthy donors that induced IFN-γ production by CD8 + T cells, thereby enhancing ICI efficacy in murine tumor models 296 . While some Clostridium species are linked to colon carcinogenesis, others, such as Roseburia intestinalis, Eubacterium hallii, Faecalibacterium prausnitzii, and Anaerostipes caccae, have demonstrated tumor-suppressive properties by activating and infiltrating intratumoral CD8+ T cells, effectively reducing tumor growth 297 . These studies suggest that the interaction between the gut microbiota and the tumor and immune system may involve more complex processes.

Early clinical trials have explored probiotics to modulate the gut microbiota and enhance antitumor immunity in cancer patients. Probiotic strains with anti-inflammatory and mucosal-protective properties, such as Lactobacillus and Bifidobacterium, have been used to mitigate chemotherapy- and radiotherapy-induced toxicity 298 – 300 . Consoli et al. reported that probiotic treatment significantly reduced IL-1β, IL-10, and IL-23A mRNA levels in colonic mucosa, leading to a lower incidence of postoperative infections 301 . A clinical trial in CRC patients found that supplementation with Bifidobacterium lactis and Lactobacillus increased butyrate-producing bacteria, particularly Faecalibacterium and Clostridiales spp., in tumor, mucosal, and fecal microbiota, further supporting the role of probiotics in enhancing antitumor responses 302 . Several ongoing clinical trials are evaluating the safety and efficacy of probiotics in combination with ICI therapy (Table 4 ) 303 – 317 . MRx0518, a flagellin-producing probiotic, activates TLR5 and NF-κB signaling pathways to exert antitumor effects 318 . A phase 1/2 trial combining MRx0518 with pembrolizumab met its primary efficacy endpoint in RCC patients, though the pharmaceutical company later withdrew from development due to financial constraints 319 . Retrospective analyses have shown that Clostridium butyricum CBM588 significantly PFS and OS in NSCLC patients receiving anti-PD-1 therapy, even among those who also received antibiotics 320 . In a phase I clinical trial ( NCT03829111 ), CBM588 significantly extended PFS in metastatic RCC patients, with a response rate of 58% when combined with an ICI, compared to 20% with ICI alone 27 . Additionally, CBM588 improved ICI efficacy in NSCLC patients treated with proton pump inhibitors (PPIs) 321 . Another promising probiotic, Bifidobacterium bifidum EDP1503, enhances the CD8 + T cell-to-Treg cell ratio, and preliminary results from a phase I clinical trial ( NCT03775850 ) suggest it is safe and well tolerated in combination with pembrolizumab 322 . Table 4 Clinical trials of probiotics interventions on immunotherapy Phase (Trial ID) Patients (n) Cancer type Probiotics Intervention Immunotherapy treatment Primary outcomes measures Ref. II( NCT04988841 ) 60 Melanoma MaaT013 αPD-1 mAb plus αCTLA-4 mAb Safety 303 II ( NCT03595683 ) 8 Melanoma EDP1503 αPD-1 mAb Response rate, AEs 304 I ( NCT03817125 ) 14 Melanoma SER-401 αPD-1 mAb AEs 225 II ( NCT04699721 ) 60 NSCLC BiFico αPD-1 mAb and chemotherapy AEs, surgical complications 305 II ( NCT04909034 ) 15 NSCLC MS-20 αPD-1 mAb AEs 306 NA ( NCT05094167 ) 46 NSCLC Kex02 αPD-1 mAb ORR 307 NA ( NCT06428422 ) 100 NSCLC BL-04 αPD-1 mAb Evaluation of Clinical Response, PFS, OS 308 II ( NCT06768931 ) 192 TNBC Biolosion αPD-1 mAb Pathological CR 309 NA ( NCT05032014 ) 46 Liver cancer Probio-M9 αPD-1 mAb ORR 310 I ( NCT05122546 ) 31 RCC CBM588 αPD-1 mAb and chemotherapy Change in stool levels of Bifidobacterium spp. 311 I ( NCT03829111 ) 30 RCC CBM588 αPD-1 mAb plus αCTLA-4 mAb Change in stool levels of Bifidobacterium 27 IV ( NCT05220124 ) 190 Urothelial bladder carcinoma Probiotic Immunotherapy PFS 312 II/III ( NCT03686202 ) 65 Solid tumors MET-4 ICI Change in microbiota, AEs 313 I ( NCT03775850 ) 69 Solid tumors EDP1503 αPD-1 mAb Safety, ORR 314 , 322 I/II ( NCT03637803 ) 63 Solid tumors MRx0518 αPD-1 mAb Safety, clinical benefit 315 I/II ( NCT04208958 ) 56 Solid tumors VE800 αPD-1 mAb Safety, ORR 316 NA ( NCT06508034 ) 30 Solid tumors VSL3 αPD-1/ PDL-1/ CTLA-4 mAb or αPD-1/PDL-1 plus chemotherapy ICI-related colitis, safety 317 NSCLC non-small-cell lung cancer, TNBC triple negative breast cancer, AEs adverse events, ORR objective response rate, PFS progression-free survival, OS overall survival, CR complete remission, ICI immune checkpoint inhibitor, RCC renal cell carcinoma.

Despite their demonstrated benefits in non-neoplastic diseases, probiotic-based cancer therapies remain underexplored, with only a limited number of clinical trials available for validation 323 , 324 . The heterogeneity of commercial probiotics and the lack of standardized quality control raise concerns about their integration with immunotherapy. Indeed, studies have demonstrated that patients who consume sufficient dietary fiber and do not utilize probiotics tend to exhibit optimal efficacy with immunotherapy 28 . Moreover, recent studies suggest that specific gut microbes may enhance anti-tumor immune responses by influencing TLS within the TME, which are closely linked to patient responses to ICI therapy 200 , 325 , 326 . These emerging insights highlight the potential for developing targeted microbiota-based interventions to optimize cancer immunotherapy.

Diet and prebiotics

Beyond direct modulation of the gut microbiota, dietary interventions can significantly influence microbial composition, bacterial metabolites, and immune responses 327 – 329 . Preclinical studies suggest that dietary strategies such as caloric restriction, intermittent fasting, high-fiber diets, ketogenic diets, and targeted micronutrient supplementation can enhance immunotherapy by reshaping gut microbiota composition 330 – 335 . For example, dietary restriction in mice promotes the accumulation of memory T cells in the bone marrow, strengthening immune responses against infections and tumors 336 . Consistent with the previous study, during chronic or intermittent fiber deficiency, the gut microbiota utilizes host-secreted mucus glycoproteins as a nutrient source, leading to a disruption of the colonic mucosal barrier and inducing a decrease in Bifidobacterium abundance and an increase in Mucococcus abundance 28 , 337 . Consequently, a poor response to anti-PD-1 therapy was observed in mice fed a low-fiber diet 28 . A ketogenic diet and its primary metabolite, 3-hydroxybutyrate, have been shown to enhance anti-PD-1 therapy by preventing PD-L1 upregulation in bone marrow cells and promoting the expansion of CXCR3+ T cells 328 . In addition, a serine/glycine-free diet has been shown to slow CRC growth while promoting the accumulation of cytotoxic T cells to enhance anti-tumor immunity. And blocking the PD-1/PD-L1 pathway further enhances the effects of this dietary approach, which highlight the potential of combining the serine/glycine-free diet with immunotherapy 338 .

Clinical studies further support the role of diet in immunotherapy outcomes. An analysis by Wastyk et al. found that high-fiber and fermented food diets influenced gut microbiota and immune function in distinct ways: high-fiber diets increased carbohydrate-active enzymes involved in glycan metabolism with moderate effects on microbial diversity, while fermented diets enhanced microbial diversity and reduced inflammatory markers 339 . A prospective study of melanoma patients undergoing ICI therapy across multiple cohorts found that higher dietary fiber intake correlated with better clinical outcomes, particularly in patients with greater bacterial diversity 65 . Additionally, dietary fiber produces SCFAs, such as butyrate, which can directly activate tumor-fighting CD8+ T cells and enhance anti-PD-1 therapy 109 , 339 , 340 . However, conflicting evidence suggests that elevated SCFA levels in peripheral blood may limit anti-CTLA-4 efficacy, indicating that the role of metabolites in antitumor immunity may vary across tissues 341 . Therefore, precision in dietary interventions is crucial for optimizing their therapeutic potential.

Prebiotics, a more targeted dietary approach, are chemically defined non-digestible fibers—primarily oligosaccharides and polysaccharides such as inulin and pectin—that selectively promote the growth of beneficial gut microbes 342 – 344 . Prebiotics improve epithelial integrity, enhance mucosal barrier function, and activate innate immune cells, contributing to improved immunotherapy outcomes 345 – 348 . Han et al. demonstrated that an oral inulin gel, designed to release in the colon, effectively modulated gut microbiota, promoted SCFA metabolism, induced systemic memory T cell responses, and strengthened anti-PD-1 therapy 349 . Meanwhile, pectin has been shown to enhance ICI efficacy through multiple mechanisms and it improves anti-PD-1 responses in colorectal cancer by increasing butyrate-producing gut flora and modulating T cell infiltration into the TME 350 . Additionally, pectin has been linked to increased abundance of mucophilic bacilli, which produce cyclic AMP and activate STING signaling, resulting in type I interferon-mediated immunity 229 .

Other prebiotics, such as polysaccharides derived from medicinal plants, have also shown promise. Ginseng polysaccharides have been found to enhance anti-PD-1 therapy by remodeling gut metabolite composition, altering tryptophan metabolism, and suppressing Treg cell responses 351 . Similarly, polyphenol-rich Kamagra supplementation in mice increased gut microbial diversity and boosted beneficial bacteria such as Ruminococcaceae, Oscillospiraceae, and Akkermansia muciniphila 352 . These changes improved the CD8+ T/Treg cell ratio in the TME and reversed ICI resistance. Unlike whole-food dietary interventions, these extracted or modified prebiotics allow for more precise modulation of gut microbiota and offer potential for targeted immunotherapy enhancements. Building on these findings, a number of clinical trials of dietary or prebiotic interventions for tumor immunotherapy are underway (Table 5 ) 353 – 367 . We look forward to the results of these clinical trials. Table 5 Clinical trials of diet and prebiotics interventions on immunotherapy Phase (Trial ID) Patients (n) Cancer type Microbial Intervention Immunotherapy treatment Primary outcomes measures Ref. II ( NCT06466434 ) 75 Melanoma PreFED ICI Efficacy 353 II ( NCT04645680 ) 50 Melanoma Dietary supplement: isocaloric high-fiber αPD-1 mAb and/or αCTLA-4 mAb Change in the gut microbiome 354 NA ( NCT06298734 ) 40 Melanoma Dietary supplement: EX/DT/COMB αPD-1 mAb /αCTLA-4 mAb /αLAG-3 mAb Change in gut microbiome diversity 355 NA ( NCT06236360 ) 30 Melanoma Dietary supplement: MINI-MD αPD-1 mAb plus αCTLA-4 mAb Efficacy 356 NA ( NCT04866810 ) 80 Melanoma Behavioral: high fiber, plant based diet+exercise Immunotherapy Feasibility 357 II ( NCT03709147 ) 64 Lung cancer Dietary supplement: FMD Chemo-immunotherapy PFS 358 NA ( NCT03700437 ) 12 NSCLC Dietary supplement: FMD Chemo-immunotherapy Feasibility, compliance 359 NA ( NCT06671613 ) 66 NSCLC Dietary supplement: FMD αPD-1/PDL-1 mAb Feasibility, compliance 360 II ( NCT05763992 ) 145 TNBC Fasting-Like Approach Chemo-immunotherapy Rate of pCR 361 NA ( NCT06610097 ) 30 TNBC Dietary supplement: high fiber Chemo-immunotherapy Species and diversity 362 NA ( NCT05083416 ) 29 HNSCC Behavioral: PNF ICI Rates of PNF compliance, change in gut microbiome and microbial metabolites 363 NA ( NCT06391099 ) 60 Melanoma, Kidney Cancer Dietary supplement: KD αPD-1 mAb AEs, adherence 364 NA ( NCT05356182 ) 30 Solid tumors Low protein diet ICI Feasibility 365 NA ( NCT05832606 ) 60 Solid tumors Dietary supplement: high fiber αPD-1 mAb and/or αCTLA-4 mAb Feasibility, irAEs 366 NA ( NCT06438588 ) 10 Solid tumors Dietary supplement: FMD ICI Symptom Measurement, AEs, physical function, QOL, fecal calprotectin 367 PreFED prebiotic food-enriched diet, EX high-intensity exercise, DT high-fiber diet, COMB combined high-intensity exercise and high-fiber diet, MD mediterranean diet, FMD fasting-mimicking diet, CR complete response, PNF prolonged nightly fasting, KD ketogenic diet, QOL quality of life, NSCLC non-small-cell lung cancer, TNBC triple negative breast cancer, HNSCC head and neck squamous cell carcinoma, AEs adverse events, irAEs immune-related Adverse Events, PFS progression-free survival, ICI immune checkpoint inhibitor.

Other strategies such as engineered microorganisms

Advancements in synthetic biology have enabled the genetic modification of bacteria to selectively target tumors. Engineered strains such as Salmonella, Escherichia coli, and Bifidobacterium can colonize the TME, exert immunogenic effects, and locally release therapeutic agents to enhance immune-mediated tumor clearance 368 – 371 . For instance, L-arginine plays a crucial role in T cell metabolism, supporting their survival and anti-tumor activity 372 . The engineered probiotic Escherichia coli Nissle 1917 has been designed to colonize tumors and convert ammonia, a metabolic byproduct, into L-arginine, thereby promoting CD4 + T and CD8 + T cell infiltration and enhancing the efficacy of anti-PD-L1 therapy 373 . Another engineered strain, SYNB1891, derived from E. coli Nissle, stimulates STING activation in antigen-presenting cells (APCs), triggering innate immune pathways that contribute to anti-tumor immunity 374 . Although a clinical trial ( NCT04167137 ) evaluating SYNB1891 in combination with atezolizumab for advanced solid tumors was paused due to funding constraints, its potential remains promising. Chowdhury et al. engineered a non-pathogenic E. coli strain to target lysis and release anti-CD47 nanoantibodies in the tumor microenvironment.CD47 is overexpressed in a variety of human cancers, and inhibition of its function promotes tumor phagocytosis by immune cells. The engineered bacteria showed significant anti-tumor effects in a mouse model, promoting the activation of tumor-infiltrating T cells, stimulating rapid tumor regression and inhibiting metastasis, thereby prolonging the survival of the mice 375 .

Recent studies have further expanded the use of engineered microorganisms in tumor immunotherapy. Engineered E. coli Nissle 1917 strains have been developed to deliver tumor-specific neoantigens, and stimulate a robust anti-tumor immune response by activating DCs, NK cells, and tumor-infiltrating T cells. This targeted approach enhances immunotherapy specificity while minimizing toxicity to normal tissues 376 . Other strategies include using engineered E. coli to deliver an IL-18 mutant, which significantly boosts CD8 + T cell and NK cell activity, suppresses tumor growth, and enhances the tumor-targeting abilities of CAR-NK cells 377 . Several engineered bacterial strains, such as ADXS11-001, Ty21a, JNJ-64041809, and VXM01, have also demonstrated potential in immunotherapy by leveraging tumor-specific antigen presentation 378 – 383 . In addition, Chen et al. genetically engineered the skin-dwelling bacterium Staphylococcus epidermidis to express tumor antigens, thereby eliciting T-cell responses against melanoma. Following colonization, these engineered bacteria induce tumor-specific T cells that mature, enter systemic circulation, and infiltrate both local and metastatic tumor sites which exert cytotoxic effects and suppress tumor growth 384 . Notably, recent studies have identified that microbiota, such as Bifidobacterium and Lactobacillus derive vesicles—such as outer membrane vesicles (OMVs) and extracellular vesicles (EVs)—that have the ability to deliver immunomodulatory molecules, antigens, or adjuvants to immune cells 385 – 387 . For example, Lactobacillus-derived EVs can inhibit colon tumor formation by modulating the SIRT5/p53 axis and thereby inhibiting colon tumor formation. These studies further expand the scope of microbiota-based oncology interventions.

Beyond engineered bacteria, other microbiota-based approaches are being explored to improve immunotherapy. Phage therapy, particularly CRISPR-Cas3 engineered phages, can modulate the gut microbiota, immune system, and TME 388 – 392 . Microbial metabolites, such as valproic acid (VPA), function as histone deacetylase (HDAC) inhibitors, influencing immune signaling pathways and promoting tumor cell apoptosis 393 . Clinical trials assessing VPA in combination with immune checkpoint inhibitors ( NCT02446431 , NCT02624128 , NCT01106872 ) are underway. Small-molecule peptides derived from the microbiota also hold promise 394 . EO2401, a microbial peptide that mimics tumor-associated antigens (TSAs), has been shown to activate memory T cells and elicit a strong immune response 395 . In the ROSALIE Phase 1/2 trial, EO2401 combined with nivolumab and bevacizumab in glioblastoma patients led to a median survival of 14.5 months and an 18-month survival rate of 43.1%, with favorable tolerability 396 .

Furthermore, the field is moving towards the development of synthetic consortia with defined immunomodulatory properties and the implementation of longitudinal studies linking microbiota dynamics to the durability of therapeutic responses. By tracking temporal changes in the microbiome and immune parameters, researchers can identify predictive biomarkers of long-term response and resistance 397 . Meanwhile, advances in synthetic biology enable the rational design of microbial communities or synthetic constructs that integrate multiple immunoregulatory mechanisms, thus providing a multi-faceted and precise approach to cancer immunotherapy. These studies underscore the potential of microbiota-based interventions in cancer treatment. Engineered microorganisms not only provide precise modulation of the TME but may also offer systemic protection against metastasis. While challenges remain, continued research and technological advancements are expected to position microbiota-based therapies as a key component of future cancer treatment strategies.

Challenges and future directions

Understanding the relationship between gut microbiota and immunotherapy remains complex. The microbiota influences immune responses through various mechanisms such as metabolite production and inflammation regulation, but these interactions are bidirectional—some microbial communities enhance immunity, while others suppress it. Moreover, variations in TMEs further complicate microbiota-driven immune modulation 398 . Many current findings are derived from animal models, yet differences in microbial composition and immune function between mice and humans limit their clinical relevance 399 , 400 . The absence of standardized research methodologies also contributes to inconsistent data, making it difficult to draw definitive conclusions. Critically, this field faces additional limitations. First, technical variability in microbiome sequencing methods—such as differences in 16S rRNA gene regions targeted, DNA extraction protocols, and sequencing platforms—can result in substantial discrepancies between studies 401 , 402 . Second, inter-trial inconsistencies, including patient selection, sample handling, and data processing, further undermine reproducibility 403 . FMT also suffers from significant ‘donor effects,’ where outcomes depend strongly on the specific microbiota composition of the donor, complicating interpretation and clinical standardization 404 . Moreover, host genetics can profoundly shape microbial composition and immune responses, yet is often underappreciated in current research designs 405 , 406 . Addressing these methodological and biological confounders is essential for the field’s progress.

Despite its promise, microbiota modulation faces significant clinical hurdles. Many studies have small sample sizes, limiting statistical power and generalizability. Standardization is another major challenge, as microbiota composition varies widely among individuals due to factors such as diet, medication use, and environmental exposure. Additionally, the lack of uniform protocols for microbiome analysis affects reproducibility. Safety concerns further complicate clinical translation—approaches like FMT may not reliably restore beneficial bacteria, and unintended microbial shifts could lead to adverse effects 407 . Addressing these issues will be critical for integrating microbiota-based strategies into clinical practice.

Advancements in genomics, metabolomics, and microbiomics are driving more precise microbiota research 408 . Non-invasive techniques, such as microbial DNA analysis from blood samples, hold potential for early cancer detection and treatment monitoring 409 . Emerging tools, including artificial gut models and ingestible biosensors, will enhance real-time microbiota analysis 410 , 411 . Multi-omics approaches combining microbiome, immune, and metabolic data may identify key microbial factors influencing immunotherapy responses, paving the way for targeted interventions. Notably, recent studies have revealed a significant influence of the gut microbiota on vaccine efficacy, particularly highlighting the roles of Bifidobacterium and Bacteroides 412 . These bacteria can interact with DCs, which are pivotal for initiating anti-tumor immune responses. Modulating the gut microbiota through dietary interventions or targeted microbial supplementation may enhance the host’s ability to recognize and respond to tumor antigens introduced by vaccines. For example, Jing et al. demonstrated that the synergistic administration of Lactobacillus rhamnosus GG and jujube powder markedly improved the efficacy of whole-cell cancer vaccines in the MC38 murine cancer model, primarily by increasing the proportion of CD8 + IFNγ + T cells 413 . Moreover, vaccine efficacy has been found to correlate with gut microbiota composition 414 . Therefore, integrating gut microbiota modulation with cancer vaccination represents a promising therapeutic strategy. As research progresses, personalized cancer immunotherapy may become a reality. Patients with an imbalanced microbiome might benefit from interventions, such as strain-specific probiotics, engineered bacterial therapies, or dietary modifications, while those with a favorable microbiota profile associated with positive immune responses may require only minor adjustments to optimize treatment outcomes. Beyond the gut, microbial communities in the oral cavity, skin, and TME may also influence immune responses, broadening the scope of personalized therapeutic strategies 415 – 417 .

Achieving clinical translation will require interdisciplinary collaboration among immunologists, microbiologists, oncologists, and data scientists. Large-scale, multi-center studies and standardized data collection methods are essential for generating clinically relevant insights. Artificial intelligence (AI) and machine learning can improve patient stratification and help identify microbiota-driven mechanisms that influence treatment outcomes. By integrating expertise across multiple fields, microbiota research can play a central role in advancing precision medicine for cancer treatment.

Conclusion

In summary, the gut microbiota plays a pivotal role in modulating cancer immunotherapy, influencing treatment efficacy, patient response, and therapy-associated toxicity. Recent advances in sequencing technologies and microbiota-targeted interventions, such as FMT, probiotics, and dietary modifications, have opened new avenues for enhancing immunotherapy outcomes. However, significant challenges remain in translating these findings into clinical practice, primarily due to inter-individual variability and the complexity of host-microbiota interactions. Future research should focus on integrating multi-omics approaches, AI, and precision medicine to establish causal relationships between microbiota composition and immunotherapy response. Additionally, exploring the mechanisms by which microbial metabolites influence tumor immune microenvironments will be crucial for developing novel therapeutic strategies. By harnessing the potential of the gut microbiota, clinicians may be able to personalize immunotherapy regimens, improve treatment efficacy, and overcome drug resistance. Ultimately, continued interdisciplinary research will be essential to fully unlock the clinical potential of microbiota-targeted interventions, paving the way for more effective and individualized cancer treatments.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

These authors contributed equally: Wanting Lei, Kexun Zhou, Ye Lei.

Acknowledgements

This research received no external funding.

Author contributions

Conceptualization, W.L. & K.Z., Software & figure, Y.L.; Validation, H.Z. & Q.L.; Writing-Original Draft Preparation, W.L. & K.Z. & Y.L.; Writing-Review & Editing, K.Z.; Visualization, H.Z. & Q.L.; Supervision, H.Z. & Q.L.

Data availability

No datasets were generated or analysed during the current study.

Competing interests

The authors declare no competing interests.

References

1. Lederberg J McCray AT ‘Ome Sweet’ Omics—a genealogical treasury of words Scientist 2001 15 8 8 Lederberg, J. & McCray, A. T. ‘Ome Sweet’ Omics—a genealogical treasury of words. Scientist 15 , 8–8 (2001).

2. Sender R Fuchs S Milo R Are we really vastly outnumbered? revisiting the ratio of bacterial to host cells in humans Cell 2016 164 337 340 26824647 10.1016/j.cell.2016.01.013 Sender, R., Fuchs, S. & Milo, R. Are we really vastly outnumbered? revisiting the ratio of bacterial to host cells in humans. Cell 164 , 337–340 (2016). 26824647 10.1016/j.cell.2016.01.013

3. Gilbert JA Current understanding of the human microbiome Nat. Med. 2018 24 392 400 29634682 10.1038/nm.4517 PMC7043356 Gilbert, J. A. et al. Current understanding of the human microbiome. Nat. Med. 24 , 392–400 (2018). 29634682 10.1038/nm.4517 PMC7043356

4. Martinez-Guryn K Leone V Chang EB Regional diversity of the gastrointestinal microbiome Cell Host Microbe 2019 26 314 324 31513770 10.1016/j.chom.2019.08.011 PMC6750279 Martinez-Guryn, K., Leone, V. & Chang, E. B. Regional diversity of the gastrointestinal microbiome. Cell Host Microbe 26 , 314–324 (2019). 31513770 10.1016/j.chom.2019.08.011 PMC6750279

5. Sender R Fuchs S Milo R Revised estimates for the number of human and bacteria cells in the body PLoS Biol. 2016 14 e1002533 27541692 10.1371/journal.pbio.1002533 PMC4991899 Sender, R., Fuchs, S. & Milo, R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol. 14 , e1002533 (2016). 27541692 10.1371/journal.pbio.1002533 PMC4991899

6. Maynard CL Elson CO Hatton RD Reciprocal interactions of the intestinal microbiota and immune system Nature 2012 489 231 241 22972296 10.1038/nature11551 PMC4492337 Maynard, C. L., Elson, C. O. & Hatton, R. D. Reciprocal interactions of the intestinal microbiota and immune system. Nature 489 , 231–241 (2012). 22972296 10.1038/nature11551 PMC4492337

7. Belkaid Y Harrison OJ Homeostatic Immunity and the Microbiota Immunity 2017 46 562 576 28423337 10.1016/j.immuni.2017.04.008 PMC5604871 Belkaid, Y. & Harrison, O. J. Homeostatic Immunity and the Microbiota. Immunity 46 , 562–576 (2017). 28423337 10.1016/j.immuni.2017.04.008 PMC5604871

8. Jugder BE Kamareddine L Watnick PI Microbiota-derived acetate activates intestinal innate immunity via the Tip60 histone acetyltransferase complex Immunity 2021 54 1683 1697.e3 34107298 10.1016/j.immuni.2021.05.017 PMC8363570 Jugder, B. E., Kamareddine, L. & Watnick, P. I. Microbiota-derived acetate activates intestinal innate immunity via the Tip60 histone acetyltransferase complex. Immunity 54 , 1683–1697.e3 (2021). 34107298 10.1016/j.immuni.2021.05.017 PMC8363570

9. Zheng D Liwinski T Elinav E Interaction between microbiota and immunity in health and disease Cell Res. 2020 30 492 506 32433595 10.1038/s41422-020-0332-7 PMC7264227 Zheng, D., Liwinski, T. & Elinav, E. Interaction between microbiota and immunity in health and disease. Cell Res. 30 , 492–506 (2020). 32433595 10.1038/s41422-020-0332-7 PMC7264227

10. Lin K Zhu L Yang L Gut and obesity/metabolic disease: Focus on microbiota metabolites MedComm 2022 3 e171 36092861 10.1002/mco2.171 PMC9437302 Lin, K., Zhu, L. & Yang, L. Gut and obesity/metabolic disease: Focus on microbiota metabolites. MedComm 3 , e171 (2022). 36092861 10.1002/mco2.171 PMC9437302

11. Oliphant K Allen-Vercoe E Macronutrient metabolism by the human gut microbiome: major fermentation by-products and their impact on host health Microbiome 2019 7 91 31196177 10.1186/s40168-019-0704-8 PMC6567490 Oliphant, K. & Allen-Vercoe, E. Macronutrient metabolism by the human gut microbiome: major fermentation by-products and their impact on host health. Microbiome 7 , 91 (2019). 31196177 10.1186/s40168-019-0704-8 PMC6567490

12. Chen Y Wang Z Chen X Chao G Zhang S The role of gut microbiota and metabolites in regulating the immune response in drug-induced enteritis J. Appl. Microbiol. 2023 134 lxad032 36806409 10.1093/jambio/lxad032 Chen, Y., Wang, Z., Chen, X., Chao, G. & Zhang, S. The role of gut microbiota and metabolites in regulating the immune response in drug-induced enteritis. J. Appl. Microbiol. 134 , lxad032 (2023). 36806409 10.1093/jambio/lxad032

13. Visekruna A Luu M The role of short-chain fatty acids and bile acids in intestinal and liver function, inflammation, and carcinogenesis Front. Cell Dev. Biol. 2021 9 703218 34381785 10.3389/fcell.2021.703218 PMC8352571 Visekruna, A. & Luu, M. The role of short-chain fatty acids and bile acids in intestinal and liver function, inflammation, and carcinogenesis. Front. Cell Dev. Biol. 9 , 703218 (2021). 34381785 10.3389/fcell.2021.703218 PMC8352571

14. Ansaldo E Farley TK Belkaid Y Control of immunity by the microbiota Annu. Rev. Immunol. 2021 39 449 479 33902310 10.1146/annurev-immunol-093019-112348 Ansaldo, E., Farley, T. K. & Belkaid, Y. Control of immunity by the microbiota. Annu. Rev. Immunol. 39 , 449–479 (2021). 33902310 10.1146/annurev-immunol-093019-112348

15. Dzutsev A Microbes and cancer Annu. Rev. Immunol. 2017 35 199 228 28142322 10.1146/annurev-immunol-051116-052133 Dzutsev, A. et al. Microbes and cancer. Annu. Rev. Immunol. 35 , 199–228 (2017). 28142322 10.1146/annurev-immunol-051116-052133

16. Zhang Y Zhang Z The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications Cell Mol. Immunol. 2020 17 807 821 32612154 10.1038/s41423-020-0488-6 PMC7395159 Zhang, Y. & Zhang, Z. The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell Mol. Immunol. 17 , 807–821 (2020). 32612154 10.1038/s41423-020-0488-6 PMC7395159

17. Sharma P Hu-Lieskovan S Wargo JA Ribas A Primary, adaptive, and acquired resistance to cancer immunotherapy Cell 2017 168 707 723 28187290 10.1016/j.cell.2017.01.017 PMC5391692 Sharma, P., Hu-Lieskovan, S., Wargo, J. A. & Ribas, A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168 , 707–723 (2017). 28187290 10.1016/j.cell.2017.01.017 PMC5391692

18. Pan C Next-generation immuno-oncology agents: current momentum shifts in cancer immunotherapy J. Hematol. Oncol. 2020 13 29 32245497 10.1186/s13045-020-00862-w PMC7119170 Pan, C. et al. Next-generation immuno-oncology agents: current momentum shifts in cancer immunotherapy. J. Hematol. Oncol. 13 , 29 (2020). 32245497 10.1186/s13045-020-00862-w PMC7119170

19. Wang M Clinical observation of the efficacy of PD-1/PD-L1 inhibitors in the treatment of patients with advanced solid tumors Immun. Inflamm. Dis. 2021 9 1584 1595 34407323 10.1002/iid3.511 PMC8589346 Wang, M. et al. Clinical observation of the efficacy of PD-1/PD-L1 inhibitors in the treatment of patients with advanced solid tumors. Immun. Inflamm. Dis. 9 , 1584–1595 (2021). 34407323 10.1002/iid3.511 PMC8589346

20. Hegde PS Chen DS Top 10 challenges in cancer immunotherapy Immunity 2020 52 17 35 31940268 10.1016/j.immuni.2019.12.011 Hegde, P. S. & Chen, D. S. Top 10 challenges in cancer immunotherapy. Immunity 52 , 17–35 (2020). 31940268 10.1016/j.immuni.2019.12.011

21. Cullin N Antunes CA Straussman R Stein-Thoeringer CK Elinav E Microbiome and cancer Cancer Cell 2021 39 1317 1341 34506740 10.1016/j.ccell.2021.08.006 Cullin, N., Antunes, C. A., Straussman, R., Stein-Thoeringer, C. K. & Elinav, E. Microbiome and cancer. Cancer Cell 39 , 1317–1341 (2021). 34506740 10.1016/j.ccell.2021.08.006

22. Fehervari Z Microbiota shape tumor immunity Nat. Immunol. 2021 22 1469 34811539 10.1038/s41590-021-01082-1 Fehervari, Z. Microbiota shape tumor immunity. Nat. Immunol. 22 , 1469 (2021). 34811539 10.1038/s41590-021-01082-1

23. Consortium I. T. P.-C. A. O. W. G. Pan-cancer analysis of whole genomes Nature 2020 578 82 93 32025007 10.1038/s41586-020-1969-6 PMC7025898 Consortium I. T. P.-C. A. O. W. G. Pan-cancer analysis of whole genomes. Nature 578 , 82–93 (2020). 32025007 10.1038/s41586-020-1969-6 PMC7025898

24. Yonekura S Cancer Induces a Stress Ileopathy Depending on β-Adrenergic Receptors and Promoting Dysbiosis that Contributes to Carcinogenesis Cancer Discov. 2022 12 1128 1151 34930787 10.1158/2159-8290.CD-21-0999 Yonekura, S. et al. Cancer Induces a Stress Ileopathy Depending on β-Adrenergic Receptors and Promoting Dysbiosis that Contributes to Carcinogenesis. Cancer Discov. 12 , 1128–1151 (2022). 34930787 10.1158/2159-8290.CD-21-0999

25. Routy B Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors Science 2018 359 91 97 29097494 10.1126/science.aan3706 Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359 , 91–97 (2018). 29097494 10.1126/science.aan3706

26. Baruch EN Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients Science 2021 371 602 609 33303685 10.1126/science.abb5920 Baruch, E. N. et al. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science 371 , 602–609 (2021). 33303685 10.1126/science.abb5920

27. Dizman N Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial Nat. Med. 2022 28 704 712 35228755 10.1038/s41591-022-01694-6 PMC9018425 Dizman, N. et al. Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial. Nat. Med. 28 , 704–712 (2022). 35228755 10.1038/s41591-022-01694-6 PMC9018425

28. Spencer CN Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response Science 2021 374 1632 1640 34941392 10.1126/science.aaz7015 PMC8970537 Spencer, C. N. et al. Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response. Science 374 , 1632–1640 (2021). 34941392 10.1126/science.aaz7015 PMC8970537

29. Liu Q Role of the gut microbiota in tumorigenesis and treatment Theranostics 2024 14 2304 2328 38646653 10.7150/thno.91700 PMC11024857 Liu, Q. et al. Role of the gut microbiota in tumorigenesis and treatment. Theranostics 14 , 2304–2328 (2024). 38646653 10.7150/thno.91700 PMC11024857

30. Blake SJ Wolf Y Boursi B Lynn DJ Role of the microbiota in response to and recovery from cancer therapy Nat. Rev. Immunol. 2024 24 308 325 37932511 10.1038/s41577-023-00951-0 Blake, S. J., Wolf, Y., Boursi, B. & Lynn, D. J. Role of the microbiota in response to and recovery from cancer therapy. Nat. Rev. Immunol. 24 , 308–325 (2024). 37932511 10.1038/s41577-023-00951-0

31. Wang M Yu F Li P Intratumor microbiota in cancer pathogenesis and immunity: from mechanisms of action to therapeutic opportunities Front. Immunol. 2023 14 1269054 37868956 10.3389/fimmu.2023.1269054 PMC10587687 Wang, M., Yu, F. & Li, P. Intratumor microbiota in cancer pathogenesis and immunity: from mechanisms of action to therapeutic opportunities. Front. Immunol. 14 , 1269054 (2023). 37868956 10.3389/fimmu.2023.1269054 PMC10587687

32. Ji H Intratumoural microbiota: from theory to clinical application Cell Commun. Signal 2023 21 164 37381018 10.1186/s12964-023-01134-z PMC10303864 Ji, H. et al. Intratumoural microbiota: from theory to clinical application. Cell Commun. Signal 21 , 164 (2023). 37381018 10.1186/s12964-023-01134-z PMC10303864

33. Cao Y Intratumoural microbiota: a new frontier in cancer development and therapy Signal Transduct. Target Ther. 2024 9 15 38195689 10.1038/s41392-023-01693-0 PMC10776793 Cao, Y. et al. Intratumoural microbiota: a new frontier in cancer development and therapy. Signal Transduct. Target Ther. 9 , 15 (2024). 38195689 10.1038/s41392-023-01693-0 PMC10776793

34. Schmid P Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial Lancet Oncol. 2020 21 44 59 31786121 10.1016/S1470-2045(19)30689-8 Schmid, P. et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 21 , 44–59 (2020). 31786121 10.1016/S1470-2045(19)30689-8

35. He K Safety and clinical activity of target-preserving anti-CTLA-4 antibody ONC-392 as monotherapy in NSCLC patients who progressed on PD(L)1-targeted immunotherapy J. Clin. Oncol. 2023 41 9024 9024 He, K., et al. Safety and clinical activity of target-preserving anti-CTLA-4 antibody ONC-392 as monotherapy in NSCLC patients who progressed on PD(L)1-targeted immunotherapy. J. Clin. Oncol. 41 , 9024–9024 (2023).

36. Zhang P Zhang G Wan X Challenges and new technologies in adoptive cell therapy J. Hematol. Oncol. 2023 16 97 37596653 10.1186/s13045-023-01492-8 PMC10439661 Zhang, P., Zhang, G. & Wan, X. Challenges and new technologies in adoptive cell therapy. J. Hematol. Oncol. 16 , 97 (2023). 37596653 10.1186/s13045-023-01492-8 PMC10439661

37. Ventola CL Cancer immunotherapy, Part 3: challenges and future trends P T 2017 42 514 521 28781505 PMC5521300 Ventola, C. L. Cancer immunotherapy, Part 3: challenges and future trends. P T 42 , 514–521 (2017). 28781505 PMC5521300

38. Zaretsky JM Mutations associated with acquired resistance to PD-1 blockade in melanoma N. Engl. J. Med. 2016 375 819 829 27433843 10.1056/NEJMoa1604958 PMC5007206 Zaretsky, J. M. et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375 , 819–829 (2016). 27433843 10.1056/NEJMoa1604958 PMC5007206

39. Sade-Feldman M Resistance to checkpoint blockade therapy through inactivation of antigen presentation Nat. Commun. 2017 8 1136 1136 29070816 10.1038/s41467-017-01062-w PMC5656607 Sade-Feldman, M. et al. Resistance to checkpoint blockade therapy through inactivation of antigen presentation. Nat. Commun. 8 , 1136–1136 (2017). 29070816 10.1038/s41467-017-01062-w PMC5656607

40. Majzner RG Mackall CL Tumor antigen escape from CAR T-cell therapy Cancer Discov. 2018 8 1219 1226 30135176 10.1158/2159-8290.CD-18-0442 Majzner, R. G. & Mackall, C. L. Tumor antigen escape from CAR T-cell therapy. Cancer Discov. 8 , 1219–1226 (2018). 30135176 10.1158/2159-8290.CD-18-0442

41. Starzer AM Preusser M Berghoff AS Immune escape mechanisms and therapeutic approaches in cancer: the cancer-immunity cycle Ther. Adv. Med Oncol. 2022 14 17588359221096219 35510032 10.1177/17588359221096219 PMC9058458 Starzer, A. M., Preusser, M. & Berghoff, A. S. Immune escape mechanisms and therapeutic approaches in cancer: the cancer-immunity cycle. Ther. Adv. Med Oncol. 14 , 17588359221096219 (2022). 35510032 10.1177/17588359221096219 PMC9058458

42. Cancer Genome Atlas Research Network Comprehensive molecular profiling of lung adenocarcinoma Nature 2014 511 543 550 25079552 10.1038/nature13385 PMC4231481 Cancer Genome Atlas Research Network Comprehensive molecular profiling of lung adenocarcinoma. Nature 511 , 543–550 (2014). 25079552 10.1038/nature13385 PMC4231481

43. Chalmers ZR Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden Genome Med. 2017 9 34 28420421 10.1186/s13073-017-0424-2 PMC5395719 Chalmers, Z. R. et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 9 , 34 (2017). 28420421 10.1186/s13073-017-0424-2 PMC5395719

44. Dubin K Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis Nat. Commun. 2016 7 10391 26837003 10.1038/ncomms10391 PMC4740747 Dubin, K. et al. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. Nat. Commun. 7 , 10391 (2016). 26837003 10.1038/ncomms10391 PMC4740747

45. Gopalakrishnan V Gut microbiome modulates response to anti- PD-1 immunotherapy in melanoma patients Science 2018 359 97 103 29097493 10.1126/science.aan4236 PMC5827966 Gopalakrishnan, V. et al. Gut microbiome modulates response to anti- PD-1 immunotherapy in melanoma patients. Science 359 , 97–103 (2018). 29097493 10.1126/science.aan4236 PMC5827966

46. Matson V The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients Science 2018 359 104 108 29302014 10.1126/science.aao3290 PMC6707353 Matson, V. et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359 , 104–108 (2018). 29302014 10.1126/science.aao3290 PMC6707353

47. Peters BA Relating the gut metagenome and metatranscriptome to immunotherapy responses in melanoma patients Genome Med. 2019 11 61 31597568 10.1186/s13073-019-0672-4 PMC6785875 Peters, B. A. et al. Relating the gut metagenome and metatranscriptome to immunotherapy responses in melanoma patients. Genome Med. 11 , 61 (2019). 31597568 10.1186/s13073-019-0672-4 PMC6785875

48. Katayama Y The role of the gut microbiome on the efficacy of immune checkpoint inhibitors in Japanese responder patients with advanced non-small cell lung cancer Transl. Lung Cancer Res. 2019 8 847 853 32010563 10.21037/tlcr.2019.10.23 PMC6976345 Katayama, Y. et al. The role of the gut microbiome on the efficacy of immune checkpoint inhibitors in Japanese responder patients with advanced non-small cell lung cancer. Transl. Lung Cancer Res. 8 , 847–853 (2019). 32010563 10.21037/tlcr.2019.10.23 PMC6976345

49. Jin Y The diversity of gut microbiome is associated with favorable responses to anti-programmed death 1 immunotherapy in Chinese patients with NSCLC J. Thorac. Oncol. 2019 14 1378 1389 31026576 10.1016/j.jtho.2019.04.007 Jin, Y. et al. The diversity of gut microbiome is associated with favorable responses to anti-programmed death 1 immunotherapy in Chinese patients with NSCLC. J. Thorac. Oncol. 14 , 1378–1389 (2019). 31026576 10.1016/j.jtho.2019.04.007

50. Zheng Y Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma J. Immunother. Cancer 2019 7 193 31337439 10.1186/s40425-019-0650-9 PMC6651993 Zheng, Y. et al. Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma. J. Immunother. Cancer 7 , 193 (2019). 31337439 10.1186/s40425-019-0650-9 PMC6651993

51. Limeta A Meta-analysis of the gut microbiota in predicting response to cancer immunotherapy in metastatic melanoma JCI Insight 2020 5 e140940 33268597 10.1172/jci.insight.140940 PMC7714408 Limeta, A. et al. Meta-analysis of the gut microbiota in predicting response to cancer immunotherapy in metastatic melanoma. JCI Insight 5 , e140940 (2020). 33268597 10.1172/jci.insight.140940 PMC7714408

52. Vernocchi P Network analysis of gut microbiome and metabolome to discover microbiota-linked biomarkers in patients affected by non-small cell lung cancer Int J. Mol. Sci. 2020 21 8730 33227982 10.3390/ijms21228730 PMC7699235 Vernocchi, P. et al. Network analysis of gut microbiome and metabolome to discover microbiota-linked biomarkers in patients affected by non-small cell lung cancer. Int J. Mol. Sci. 21 , 8730 (2020). 33227982 10.3390/ijms21228730 PMC7699235

53. Peng Z The gut microbiome is associated with clinical response to anti-PD-1/PD-L1 immunotherapy in gastrointestinal cancer Cancer Immunol. Res. 2020 8 1251 1261 32855157 10.1158/2326-6066.CIR-19-1014 Peng, Z. et al. The gut microbiome is associated with clinical response to anti-PD-1/PD-L1 immunotherapy in gastrointestinal cancer. Cancer Immunol. Res. 8 , 1251–1261 (2020). 32855157 10.1158/2326-6066.CIR-19-1014

54. Salgia NJ Stool microbiome profiling of patients with metastatic renal cell carcinoma receiving anti-PD-1 immune checkpoint inhibitors Eur. Urol. 2020 78 498 502 32828600 10.1016/j.eururo.2020.07.011 Salgia, N. J. et al. Stool microbiome profiling of patients with metastatic renal cell carcinoma receiving anti-PD-1 immune checkpoint inhibitors. Eur. Urol. 78 , 498–502 (2020). 32828600 10.1016/j.eururo.2020.07.011

55. Davar D Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients Science 2021 371 595 602 33542131 10.1126/science.abf3363 PMC8097968 Davar, D. et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science 371 , 595–602 (2021). 33542131 10.1126/science.abf3363 PMC8097968

56. Andrews MC Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade Nat. Med. 2021 27 1432 1441 34239137 10.1038/s41591-021-01406-6 PMC11107795 Andrews, M. C. et al. Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade. Nat. Med. 27 , 1432–1441 (2021). 34239137 10.1038/s41591-021-01406-6 PMC11107795

57. Takada K Clinical impact of probiotics on the efficacy of anti-PD-1monotherapy in patients with non-small cell lung cancer: a multicenter retrospective survival analysis study with inverse probability of treatment weighting Int. J. Cancer 2021 149 473 482 33720422 10.1002/ijc.33557 Takada, K. et al. Clinical impact of probiotics on the efficacy of anti-PD-1monotherapy in patients with non-small cell lung cancer: a multicenter retrospective survival analysis study with inverse probability of treatment weighting. Int. J. Cancer 149 , 473–482 (2021). 33720422 10.1002/ijc.33557

58. Chau J Prospective correlation between the patient microbiome with response to and development of immune-mediated adverse effects to immunotherapy in lung cancer BMC Cancer 2021 21 808 34256732 10.1186/s12885-021-08530-z PMC8278634 Chau, J. et al. Prospective correlation between the patient microbiome with response to and development of immune-mediated adverse effects to immunotherapy in lung cancer. BMC Cancer 21 , 808 (2021). 34256732 10.1186/s12885-021-08530-z PMC8278634

59. Mao J Gut microbiome is associated with the clinical response to anti-PD-1 based immunotherapy in hepatobiliary cancers J. Immunother. Cancer 2021 9 e003334 34873013 10.1136/jitc-2021-003334 PMC8650503 Mao, J. et al. Gut microbiome is associated with the clinical response to anti-PD-1 based immunotherapy in hepatobiliary cancers. J. Immunother. Cancer 9 , e003334 (2021). 34873013 10.1136/jitc-2021-003334 PMC8650503

60. Chung MW Gut microbiome composition can predict the response to nivolumab in advanced hepatocellular carcinoma patients World J. Gastroenterol. 2021 27 7340 7349 34876793 10.3748/wjg.v27.i42.7340 PMC8611200 Chung, M. W. et al. Gut microbiome composition can predict the response to nivolumab in advanced hepatocellular carcinoma patients. World J. Gastroenterol. 27 , 7340–7349 (2021). 34876793 10.3748/wjg.v27.i42.7340 PMC8611200

61. Yang D Blood microbiota diversity determines response of advanced colorectal cancer to chemotherapy combined with adoptive T cell immunotherapy Oncoimmunology 2021 10 1976953 34595059 10.1080/2162402X.2021.1976953 PMC8477924 Yang, D. et al. Blood microbiota diversity determines response of advanced colorectal cancer to chemotherapy combined with adoptive T cell immunotherapy. Oncoimmunology 10 , 1976953 (2021). 34595059 10.1080/2162402X.2021.1976953 PMC8477924

62. Yin H The commensal consortium of the gut microbiome is associated with favorable responses to anti-programmed death protein 1 (PD-1) therapy in thoracic neoplasms Cancer Biol. Med. 2021 18 1040 33960176 10.20892/j.issn.2095-3941.2020.0450 PMC8610161 Yin, H. et al. The commensal consortium of the gut microbiome is associated with favorable responses to anti-programmed death protein 1 (PD-1) therapy in thoracic neoplasms. Cancer Biol. Med. 18 , 1040 (2021). 33960176 10.20892/j.issn.2095-3941.2020.0450 PMC8610161

63. Lee KA Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma Nat. Med. 2022 28 535 544 35228751 10.1038/s41591-022-01695-5 PMC8938272 Lee, K. A. et al. Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma. Nat. Med. 28 , 535–544 (2022). 35228751 10.1038/s41591-022-01695-5 PMC8938272

64. McCulloch JA Intestinal microbiota signatures of clinical response and immune-related adverse events in melanoma patients treated with anti-PD-1 Nat. Med. 2022 28 545 556 35228752 10.1038/s41591-022-01698-2 PMC10246505 McCulloch, J. A. et al. Intestinal microbiota signatures of clinical response and immune-related adverse events in melanoma patients treated with anti-PD-1. Nat. Med. 28 , 545–556 (2022). 35228752 10.1038/s41591-022-01698-2 PMC10246505

65. Simpson RC Diet-driven microbial ecology underpins associations between cancer immunotherapy outcomes and the gut microbiome Nat. Med. 2022 28 2344 2352 36138151 10.1038/s41591-022-01965-2 Simpson, R. C. et al. Diet-driven microbial ecology underpins associations between cancer immunotherapy outcomes and the gut microbiome. Nat. Med. 28 , 2344–2352 (2022). 36138151 10.1038/s41591-022-01965-2

66. Newsome RC Interaction of bacterial genera associated with therapeutic response to immune checkpoint PD-1 blockade in a United States cohort Genome Med. 2022 14 35 35346337 10.1186/s13073-022-01037-7 PMC8961902 Newsome, R. C. et al. Interaction of bacterial genera associated with therapeutic response to immune checkpoint PD-1 blockade in a United States cohort. Genome Med. 14 , 35 (2022). 35346337 10.1186/s13073-022-01037-7 PMC8961902

67. Chu S Airway Fusobacterium is associated with poor response to immunotherapy in lung cancer Onco Targets Ther. 2022 15 201 213 35250279 10.2147/OTT.S348382 PMC8896836 Chu, S. et al. Airway Fusobacterium is associated with poor response to immunotherapy in lung cancer. Onco Targets Ther. 15 , 201–213 (2022). 35250279 10.2147/OTT.S348382 PMC8896836

68. Lee PC Gut microbiota and metabolites associate with outcomes of immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma J. Immunother. Cancer 2022 10 e004779 35738801 10.1136/jitc-2022-004779 PMC9226985 Lee, P. C. et al. Gut microbiota and metabolites associate with outcomes of immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma. J. Immunother. Cancer 10 , e004779 (2022). 35738801 10.1136/jitc-2022-004779 PMC9226985

69. Che H Association of Helicobacter pylori infection with survival outcomes in advanced gastric cancer patients treated with immune checkpoint inhibitors BMC Cancer 2022 22 904 35986342 10.1186/s12885-022-10004-9 PMC9389789 Che, H. et al. Association of Helicobacter pylori infection with survival outcomes in advanced gastric cancer patients treated with immune checkpoint inhibitors. BMC Cancer 22 , 904 (2022). 35986342 10.1186/s12885-022-10004-9 PMC9389789

70. Peiffer LB Composition of gastrointestinal microbiota in association with treatment response in individuals with metastatic castrate resistant prostate cancer progressing on enzalutamide and initiating treatment with anti-PD-1 (pembrolizumab) Neoplasia 2022 32 100822 35908379 10.1016/j.neo.2022.100822 PMC9340532 Peiffer, L. B. et al. Composition of gastrointestinal microbiota in association with treatment response in individuals with metastatic castrate resistant prostate cancer progressing on enzalutamide and initiating treatment with anti-PD-1 (pembrolizumab). Neoplasia 32 , 100822 (2022). 35908379 10.1016/j.neo.2022.100822 PMC9340532

71. Smith M Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy Nat. Med. 2022 28 713 723 35288695 10.1038/s41591-022-01702-9 PMC9434490 Smith, M. et al. Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy. Nat. Med. 28 , 713–723 (2022). 35288695 10.1038/s41591-022-01702-9 PMC9434490

72. Hu Y CAR-T cell therapy-related cytokine release syndrome and therapeutic response is modulated by the gut microbiome in hematologic malignancies Nat. Commun. 2022 13 5313 36085303 10.1038/s41467-022-32960-3 PMC9461447 Hu, Y. et al. CAR-T cell therapy-related cytokine release syndrome and therapeutic response is modulated by the gut microbiome in hematologic malignancies. Nat. Commun. 13 , 5313 (2022). 36085303 10.1038/s41467-022-32960-3 PMC9461447

73. Xu L Genomic and microbial factors affect the prognosis of anti-pd-1 immunotherapy in nasopharyngeal carcinoma Front. Oncol. 2022 12 953884 36059644 10.3389/fonc.2022.953884 PMC9428750 Xu, L. et al. Genomic and microbial factors affect the prognosis of anti-pd-1 immunotherapy in nasopharyngeal carcinoma. Front. Oncol. 12 , 953884 (2022). 36059644 10.3389/fonc.2022.953884 PMC9428750

74. Routy B Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial Nat. Med. 2023 29 2121 2132 37414899 10.1038/s41591-023-02453-x Routy, B. et al. Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial. Nat. Med. 29 , 2121–2132 (2023). 37414899 10.1038/s41591-023-02453-x

75. Dora D Non-small cell lung cancer patients treated with Anti-PD1 immunotherapy show distinct microbial signatures and metabolic pathways according to progression-free survival and PD-L1 status Oncoimmunology 2023 12 2204746 37197440 10.1080/2162402X.2023.2204746 PMC10184596 Dora, D. et al. Non-small cell lung cancer patients treated with Anti-PD1 immunotherapy show distinct microbial signatures and metabolic pathways according to progression-free survival and PD-L1 status. Oncoimmunology 12 , 2204746 (2023). 37197440 10.1080/2162402X.2023.2204746 PMC10184596

76. Haberman Y Gut microbial signature in lung cancer patients highlights specific taxa as predictors for durable clinical benefit Sci. Rep. 2023 13 2007 36737654 10.1038/s41598-023-29136-4 PMC9898251 Haberman, Y. et al. Gut microbial signature in lung cancer patients highlights specific taxa as predictors for durable clinical benefit. Sci. Rep. 13 , 2007 (2023). 36737654 10.1038/s41598-023-29136-4 PMC9898251

77. Han Z The gut microbiome affects response of treatments in HER2-negative advanced gastric cancer Clin. Transl. Med. 2023 13 e1312 37381590 10.1002/ctm2.1312 PMC10307992 Han, Z. et al. The gut microbiome affects response of treatments in HER2-negative advanced gastric cancer. Clin. Transl. Med. 13 , e1312 (2023). 2023. 37381590 10.1002/ctm2.1312 PMC10307992

78. Zhao W Fecal microbiota transplantation plus tislelizumab and fruquintinib in refractory microsatellite stable metastatic colorectal cancer: an open-label, single-arm, phase II trial (RENMIN-215) EClinicalMedicine 2023 66 102315 38024475 10.1016/j.eclinm.2023.102315 PMC10679864 Zhao, W. et al. Fecal microbiota transplantation plus tislelizumab and fruquintinib in refractory microsatellite stable metastatic colorectal cancer: an open-label, single-arm, phase II trial (RENMIN-215). EClinicalMedicine 66 , 102315 (2023). 38024475 10.1016/j.eclinm.2023.102315 PMC10679864

79. Stein-Thoeringer CK A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy Nat. Med. 2023 29 906 916 36914893 10.1038/s41591-023-02234-6 PMC10121864 Stein-Thoeringer, C. K. et al. A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy. Nat. Med. 29 , 906–916 (2023). 36914893 10.1038/s41591-023-02234-6 PMC10121864

80. Björk JR Longitudinal gut microbiome changes in immune checkpoint blockade-treated advanced melanoma Nat. Med. 2024 30 785 796 38365950 10.1038/s41591-024-02803-3 PMC10957474 Björk, J. R. et al. Longitudinal gut microbiome changes in immune checkpoint blockade-treated advanced melanoma. Nat. Med. 30 , 785–796 (2024). 38365950 10.1038/s41591-024-02803-3 PMC10957474

81. Sun L Gut microbiota and metabolites associated with immunotherapy efficacy in extensive-stage small cell lung cancer: a pilot study J. Thorac. Dis. 2024 16 6936 6954 39552845 10.21037/jtd-24-1201 PMC11565349 Sun, L. et al. Gut microbiota and metabolites associated with immunotherapy efficacy in extensive-stage small cell lung cancer: a pilot study. J. Thorac. Dis. 16 , 6936–6954 (2024). 39552845 10.21037/jtd-24-1201 PMC11565349

82. Sitthideatphaiboon P Dietary pattern and the corresponding gut microbiome in response to immunotherapy in Thai patients with advanced non-small cell lung cancer (NSCLC) Sci. Rep. 2024 14 27791 39537963 10.1038/s41598-024-79339-6 PMC11561170 Sitthideatphaiboon, P. et al. Dietary pattern and the corresponding gut microbiome in response to immunotherapy in Thai patients with advanced non-small cell lung cancer (NSCLC). Sci. Rep. 14 , 27791 (2024). 39537963 10.1038/s41598-024-79339-6 PMC11561170

83. Yang Z Gut microbiome model predicts response to neoadjuvant immunotherapy plus chemoradiotherapy in rectal cancer Med 2024 5 1293 1306.e4 39047732 10.1016/j.medj.2024.07.002 Yang, Z. et al. Gut microbiome model predicts response to neoadjuvant immunotherapy plus chemoradiotherapy in rectal cancer. Med 5 , 1293–1306.e4 (2024). 39047732 10.1016/j.medj.2024.07.002

84. Zhang M A gut microbiota rheostat forecasts responsiveness to PD-L1 and VEGF blockade in mesothelioma Nat. Commun. 2024 15 7187 39168966 10.1038/s41467-024-49842-5 PMC11339264 Zhang, M. et al. A gut microbiota rheostat forecasts responsiveness to PD-L1 and VEGF blockade in mesothelioma. Nat. Commun. 15 , 7187 (2024). 39168966 10.1038/s41467-024-49842-5 PMC11339264

85. Rosario SR Integrative multi-omics analysis uncovers tumor-immune-gut axis influencing immunotherapy outcomes in ovarian cancer Nat. Commun. 2024 15 10609 39638782 10.1038/s41467-024-54565-8 PMC11621351 Rosario, S. R. et al. Integrative multi-omics analysis uncovers tumor-immune-gut axis influencing immunotherapy outcomes in ovarian cancer. Nat. Commun. 15 , 10609 (2024). 39638782 10.1038/s41467-024-54565-8 PMC11621351

86. Davar D Neoadjuvant vidutolimod and nivolumab in high-risk resectable melanoma: a prospective phase II trial Cancer Cell 2024 42 1898 1918.e12 39486411 10.1016/j.ccell.2024.10.007 PMC11560503 Davar, D. et al. Neoadjuvant vidutolimod and nivolumab in high-risk resectable melanoma: a prospective phase II trial. Cancer Cell 42 , 1898–1918.e12 (2024). 39486411 10.1016/j.ccell.2024.10.007 PMC11560503

87. Gao, W. et al. Predictable regulation of gut microbiome in immunotherapeutic efficacy of gastric cancer. Genes Immun. 26 , 1–8 (2024). 10.1038/s41435-024-00306-2 39533019

88. Macandog ADG Longitudinal analysis of the gut microbiota during anti-PD-1 therapy reveals stable microbial features of response in melanoma patients Cell Host Microbe 2025 32 2004 2018.e9 10.1016/j.chom.2024.10.006 PMC11629153 39481388 Macandog, A. D. G. et al. Longitudinal analysis of the gut microbiota during anti-PD-1 therapy reveals stable microbial features of response in melanoma patients. Cell Host Microbe 32 , 2004–2018.e9 (2025). 10.1016/j.chom.2024.10.006 PMC11629153 39481388

89. Yu Z Lachnoclostridium intestinal flora is associated with immunotherapy efficacy in nasopharyngeal carcinoma Head. Neck 2025 47 269 281 39135356 10.1002/hed.27917 Yu, Z. et al. Lachnoclostridium intestinal flora is associated with immunotherapy efficacy in nasopharyngeal carcinoma. Head. Neck 47 , 269–281 (2025). 39135356 10.1002/hed.27917

90. Furusawa Y Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells Nature 2013 504 446 450 24226770 10.1038/nature12721 Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504 , 446–450 (2013). 24226770 10.1038/nature12721

91. Smith PM The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis Science 2013 341 569 573 23828891 10.1126/science.1241165 PMC3807819 Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341 , 569–573 (2013). 23828891 10.1126/science.1241165 PMC3807819

92. Viaud S The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide Science 2013 342 971 976 24264990 10.1126/science.1240537 PMC4048947 Viaud, S. et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 342 , 971–976 (2013). 24264990 10.1126/science.1240537 PMC4048947

93. Sivan A Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy Science 2015 350 1084 1089 26541606 10.1126/science.aac4255 PMC4873287 Sivan, A. et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350 , 1084–1089 (2015). 26541606 10.1126/science.aac4255 PMC4873287

94. Vétizou M Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota Science 2015 350 1079 1084 26541610 10.1126/science.aad1329 PMC4721659 Vétizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350 , 1079–1084 (2015). 26541610 10.1126/science.aad1329 PMC4721659

95. Pinato DJ Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer JAMA Oncol. 2019 5 1774 1778 31513236 10.1001/jamaoncol.2019.2785 PMC6743060 Pinato, D. J. et al. Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer. JAMA Oncol. 5 , 1774–1778 (2019). 31513236 10.1001/jamaoncol.2019.2785 PMC6743060

96. Elkrief A Antibiotics are associated with decreased progression-free survival of advanced melanoma patients treated with immune checkpoint inhibitors Oncoimmunology 2019 8 e1568812 30906663 10.1080/2162402X.2019.1568812 PMC6422373 Elkrief, A. et al. Antibiotics are associated with decreased progression-free survival of advanced melanoma patients treated with immune checkpoint inhibitors. Oncoimmunology 8 , e1568812 (2019). 30906663 10.1080/2162402X.2019.1568812 PMC6422373

97. Zhu, X. et al. Interplay between gut microbial communities and metabolites modulates pan-cancer immunotherapy responses. Cell Metab. S1550-4131(24)00495-9 (2025). 10.1016/j.cmet.2024.12.013 39909032

98. Gunjur A A gut microbial signature for combination immune checkpoint blockade across cancer types Nat. Med. 2024 30 797 809 38429524 10.1038/s41591-024-02823-z PMC10957475 Gunjur, A. et al. A gut microbial signature for combination immune checkpoint blockade across cancer types. Nat. Med. 30 , 797–809 (2024). 38429524 10.1038/s41591-024-02823-z PMC10957475

99. Byrd AL Gut microbiome stability and dynamics in healthy donors and patients with non-gastrointestinal cancers J. Exp. Med 2021 218 e20200606 33175106 10.1084/jem.20200606 PMC7664509 Byrd, A. L. et al. Gut microbiome stability and dynamics in healthy donors and patients with non-gastrointestinal cancers. J. Exp. Med 218 , e20200606 (2021). 33175106 10.1084/jem.20200606 PMC7664509

100. Kartal E A faecal microbiota signature with high specificity for pancreatic cancer Gut 2022 71 1359 1372 35260444 10.1136/gutjnl-2021-324755 PMC9185815 Kartal, E. et al. A faecal microbiota signature with high specificity for pancreatic cancer. Gut 71 , 1359–1372 (2022). 35260444 10.1136/gutjnl-2021-324755 PMC9185815

101. Terrisse S Intestinal microbiota influences clinical outcome and side effects of early breast cancer treatment Cell Death Differ. 2021 28 2778 2796 33963313 10.1038/s41418-021-00784-1 PMC8408230 Terrisse, S. et al. Intestinal microbiota influences clinical outcome and side effects of early breast cancer treatment. Cell Death Differ. 28 , 2778–2796 (2021). 33963313 10.1038/s41418-021-00784-1 PMC8408230

102. He D Response to PD-1-based immunotherapy for non- small cell lung cancer altered by gut microbiota Oncol. Ther. 2021 9 647 657 34664203 10.1007/s40487-021-00171-3 PMC8593091 He, D. et al. Response to PD-1-based immunotherapy for non- small cell lung cancer altered by gut microbiota. Oncol. Ther. 9 , 647–657 (2021). 34664203 10.1007/s40487-021-00171-3 PMC8593091

103. Derosa L Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non- small-cell lung cancer Nat. Med. 2022 28 315 324 35115705 10.1038/s41591-021-01655-5 PMC9330544 Derosa, L. et al. Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non- small-cell lung cancer. Nat. Med. 28 , 315–324 (2022). 35115705 10.1038/s41591-021-01655-5 PMC9330544

104. Zepeda-Rivera M A distinct Fusobacterium nucleatum clade dominates the colorectal cancer niche Nature 2024 628 424 432 38509359 10.1038/s41586-024-07182-w PMC11006615 Zepeda-Rivera, M. et al. A distinct Fusobacterium nucleatum clade dominates the colorectal cancer niche. Nature 628 , 424–432 (2024). 38509359 10.1038/s41586-024-07182-w PMC11006615

105. Baulu E Gardet C Chuvin N Depil S TCR-engineered T cell therapy in solid tumors: State of the art and perspectives Sci. Adv. 2023 9 eadf3700 36791198 10.1126/sciadv.adf3700 PMC9931212 Baulu, E., Gardet, C., Chuvin, N. & Depil, S. TCR-engineered T cell therapy in solid tumors: State of the art and perspectives. Sci. Adv. 9 , eadf3700 (2023). 36791198 10.1126/sciadv.adf3700 PMC9931212

106. Uslu U Castelli S June CH CAR T cell combination therapies to treat cancer Cancer Cell 2024 42 1319 1325 39059390 10.1016/j.ccell.2024.07.002 Uslu, U., Castelli, S. & June, C. H. CAR T cell combination therapies to treat cancer. Cancer Cell 42 , 1319–1325 (2024). 39059390 10.1016/j.ccell.2024.07.002

107. Paulos CM Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling J. Clin. Invest. 2007 117 2197 2204 17657310 10.1172/JCI32205 PMC1924500 Paulos, C. M. et al. Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling. J. Clin. Invest. 117 , 2197–2204 (2007). 17657310 10.1172/JCI32205 PMC1924500

108. Uribe-Herranz M Gut microbiota modulates adoptive cell therapy via CD8α dendritic cells and IL-12 JCI Insight 2018 3 e94952 29467322 10.1172/jci.insight.94952 PMC5916241 Uribe-Herranz, M. et al. Gut microbiota modulates adoptive cell therapy via CD8α dendritic cells and IL-12. JCI Insight 3 , e94952 (2018). 29467322 10.1172/jci.insight.94952 PMC5916241

109. Ma C Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells Science 2018 360 eaan5931 29798856 10.1126/science.aan5931 PMC6407885 Ma, C. et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science 360 , eaan5931 (2018). 29798856 10.1126/science.aan5931 PMC6407885

110. Luu M Regulation of the effector function of CD8+ T cells by gut microbiota-derived metabolite butyrate Sci. Rep. 2018 8 14430 30258117 10.1038/s41598-018-32860-x PMC6158259 Luu, M. et al. Regulation of the effector function of CD8+ T cells by gut microbiota-derived metabolite butyrate. Sci. Rep. 8 , 14430 (2018). 30258117 10.1038/s41598-018-32860-x PMC6158259

111. He Y Gut microbial metabolites facilitate anticancer therapy efficacy by modulating cytotoxic CD8+ T cell immunity Cell Metab. 2021 33 988 1000.e7 33761313 10.1016/j.cmet.2021.03.002 He, Y. et al. Gut microbial metabolites facilitate anticancer therapy efficacy by modulating cytotoxic CD8+ T cell immunity. Cell Metab. 33 , 988–1000.e7 (2021). 33761313 10.1016/j.cmet.2021.03.002

112. Luu M Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer Nat. Commun. 2021 12 4077 34210970 10.1038/s41467-021-24331-1 PMC8249424 Luu, M. et al. Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer. Nat. Commun. 12 , 4077 (2021). 34210970 10.1038/s41467-021-24331-1 PMC8249424

113. Asokan S Cullin N Stein-Thoeringer CK Elinav E CAR-T cell therapy and the gut microbiota Cancers (Basel) 2023 15 794 36765752 10.3390/cancers15030794 PMC9913364 Asokan, S., Cullin, N., Stein-Thoeringer, C. K. & Elinav, E. CAR-T cell therapy and the gut microbiota. Cancers (Basel) 15 , 794 (2023). 36765752 10.3390/cancers15030794 PMC9913364

114. Cremonesi E Gut microbiota modulate T cell trafficking into human colorectal cancer Gut 2018 67 1984 1994 29437871 10.1136/gutjnl-2016-313498 Cremonesi, E. et al. Gut microbiota modulate T cell trafficking into human colorectal cancer. Gut 67 , 1984–1994 (2018). 29437871 10.1136/gutjnl-2016-313498

115. Zhu C Remolding the tumor microenvironment by bacteria augments adoptive T cell therapy in advanced-stage solid tumors Signal Transduct. Target Ther. 2024 9 307 39572541 10.1038/s41392-024-02028-3 PMC11582571 Zhu, C. et al. Remolding the tumor microenvironment by bacteria augments adoptive T cell therapy in advanced-stage solid tumors. Signal Transduct. Target Ther. 9 , 307 (2024). 39572541 10.1038/s41392-024-02028-3 PMC11582571

116. Pulendran B Arunachalam PS O’Hagan DT Emerging concepts in the science of vaccine adjuvants Nat. Rev. Drug Discov. 2021 20 454 475 33824489 10.1038/s41573-021-00163-y PMC8023785 Pulendran, B., Arunachalam, P. S. & O’Hagan, D. T. Emerging concepts in the science of vaccine adjuvants. Nat. Rev. Drug Discov. 20 , 454–475 (2021). 33824489 10.1038/s41573-021-00163-y PMC8023785

117. Shirota H Klinman DM Recent progress concerning CpG DNA and its use as a vaccine adjuvant Expert Rev. Vaccines 2014 13 299 312 24308579 10.1586/14760584.2014.863715 PMC6335645 Shirota, H. & Klinman, D. M. Recent progress concerning CpG DNA and its use as a vaccine adjuvant. Expert Rev. Vaccines 13 , 299–312 (2014). 24308579 10.1586/14760584.2014.863715 PMC6335645

118. Ribas A Overcoming PD-1 blockade resistance with CpG-A toll-like receptor 9 agonist vidutolimod in patients with metastatic melanoma Cancer Discov. 2021 11 2998 3007 34326162 10.1158/2159-8290.CD-21-0425 PMC8799774 Ribas, A. et al. Overcoming PD-1 blockade resistance with CpG-A toll-like receptor 9 agonist vidutolimod in patients with metastatic melanoma. Cancer Discov. 11 , 2998–3007 (2021). 34326162 10.1158/2159-8290.CD-21-0425 PMC8799774

119. Guiducci C Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection Cancer Res. 2005 65 3437 3446 15833879 10.1158/0008-5472.CAN-04-4262 Guiducci, C. et al. Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. Cancer Res. 65 , 3437–3446 (2005). 15833879 10.1158/0008-5472.CAN-04-4262

120. Iida N Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment Science 2013 342 967 970 24264989 10.1126/science.1240527 PMC6709532 Iida, N. et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 342 , 967–970 (2013). 24264989 10.1126/science.1240527 PMC6709532

121. Levy M Kolodziejczyk AA Thaiss CA Elinav E Dysbiosis and the immune system Nat. Rev. Immunol. 2017 17 219 232 28260787 10.1038/nri.2017.7 Levy, M., Kolodziejczyk, A. A., Thaiss, C. A. & Elinav, E. Dysbiosis and the immune system. Nat. Rev. Immunol. 17 , 219–232 (2017). 28260787 10.1038/nri.2017.7

122. Rescigno M Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria Nat. Immunol. 2001 2 361 367 11276208 10.1038/86373 Rescigno, M. et al. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat. Immunol. 2 , 361–367 (2001). 11276208 10.1038/86373

123. Deng H A novel strain of Bacteroides fragilis enhances phagocytosis and polarises M1 macrophages Sci. Rep. 2016 6 29401 27381366 10.1038/srep29401 PMC4933912 Deng, H. et al. A novel strain of Bacteroides fragilis enhances phagocytosis and polarises M1 macrophages. Sci. Rep. 6 , 29401 (2016). 27381366 10.1038/srep29401 PMC4933912

124. Ramanan D Tang MS Bowcutt R Loke P Cadwell K Bacterial sensor Nod2 prevents inflammation of the small intestine by restricting the expansion of the commensal Bacteroides vulgatus Immunity 2014 41 311 324 25088769 10.1016/j.immuni.2014.06.015 PMC4238935 Ramanan, D., Tang, M. S., Bowcutt, R., Loke, P. & Cadwell, K. Bacterial sensor Nod2 prevents inflammation of the small intestine by restricting the expansion of the commensal Bacteroides vulgatus. Immunity 41 , 311–324 (2014). 25088769 10.1016/j.immuni.2014.06.015 PMC4238935

125. Birchenough GM Nystrom EE Johansson ME Hansson GC A sentinel goblet cell guards the colonic crypt by triggering Nlrp6-dependent Muc2 secretion Science 2016 352 1535 1542 27339979 10.1126/science.aaf7419 PMC5148821 Birchenough, G. M., Nystrom, E. E., Johansson, M. E. & Hansson, G. C. A sentinel goblet cell guards the colonic crypt by triggering Nlrp6-dependent Muc2 secretion. Science 352 , 1535–1542 (2016). 27339979 10.1126/science.aaf7419 PMC5148821

126. Castro-Dopico T Anti-commensal IgG drives intestinal inflammation and Type 17 immunity in ulcerative colitis Immunity 2019 50 1099 1114.e10 30876876 10.1016/j.immuni.2019.02.006 PMC6477154 Castro-Dopico, T. et al. Anti-commensal IgG drives intestinal inflammation and Type 17 immunity in ulcerative colitis. Immunity 50 , 1099–1114.e10 (2019). 30876876 10.1016/j.immuni.2019.02.006 PMC6477154

127. Qiu Y Lactobacillus plantarum enhanced IL-22 production in Natural Killer (NK) cells that protect the integrity of intestinal epithelial cell barrier damaged by enterotoxigenic Escherichia coli Int J. Mol. Sci. 2017 18 2409 29137183 10.3390/ijms18112409 PMC5713377 Qiu, Y. et al. Lactobacillus plantarum enhanced IL-22 production in Natural Killer (NK) cells that protect the integrity of intestinal epithelial cell barrier damaged by enterotoxigenic Escherichia coli. Int J. Mol. Sci. 18 , 2409 (2017). 29137183 10.3390/ijms18112409 PMC5713377

128. Guo X Innate lymphoid cells control early colonization resistance against intestinal pathogens through ID2-dependent regulation of the microbiota Immunity 2015 42 731 743 25902484 10.1016/j.immuni.2015.03.012 PMC4725053 Guo, X. et al. Innate lymphoid cells control early colonization resistance against intestinal pathogens through ID2-dependent regulation of the microbiota. Immunity 42 , 731–743 (2015). 25902484 10.1016/j.immuni.2015.03.012 PMC4725053

129. Hu C Gut microbiota-derived short-chain fatty acids regulate group 3 innate lymphoid cells in HCC Hepatology 2023 77 48 64 35262957 10.1002/hep.32449 PMC9970019 Hu, C. et al. Gut microbiota-derived short-chain fatty acids regulate group 3 innate lymphoid cells in HCC. Hepatology 77 , 48–64 (2023). 35262957 10.1002/hep.32449 PMC9970019

130. Polonio, C. M. et al. 2025. The aryl hydrocarbon receptor: a rehabilitated target for therapeutic immune modulation. Nat Rev Drug Discov (2025). Online ahead of print. 10.1038/s41573-025-01172-x PMC12875337 40247142

131. Balachandran VP Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer Nature 2017 551 512 516 29132146 10.1038/nature24462 PMC6145146 Balachandran, V. P. et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 551 , 512–516 (2017). 29132146 10.1038/nature24462 PMC6145146

132. Davar D Zarour HM Facts and hopes for gut microbiota interventions in cancer immunotherapy Clin. Cancer Res 2022 28 4370 4384 35748749 10.1158/1078-0432.CCR-21-1129 PMC9561605 Davar, D. & Zarour, H. M. Facts and hopes for gut microbiota interventions in cancer immunotherapy. Clin. Cancer Res 28 , 4370–4384 (2022). 2022. 35748749 10.1158/1078-0432.CCR-21-1129 PMC9561605

133. Kalaora S Identification of bacteria-derived HLA-bound peptides in melanoma Nature 2021 592 138 143 33731925 10.1038/s41586-021-03368-8 PMC9717498 Kalaora, S. et al. Identification of bacteria-derived HLA-bound peptides in melanoma. Nature 592 , 138–143 (2021). 33731925 10.1038/s41586-021-03368-8 PMC9717498

134. Sanchez JF Maknojia AA King KY Blood and guts: how the intestinal microbiome shapes hematopoiesis and treatment of hematologic disease Blood 2024 143 1689 1701 38364184 10.1182/blood.2023021174 PMC11103099 Sanchez, J. F., Maknojia, A. A. & King, K. Y. Blood and guts: how the intestinal microbiome shapes hematopoiesis and treatment of hematologic disease. Blood 143 , 1689–1701 (2024). 38364184 10.1182/blood.2023021174 PMC11103099

135. Atarashi K Induction of colonic regulatory T cells by indigenous Clostridium species Science 2011 331 337 341 21205640 10.1126/science.1198469 PMC3969237 Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331 , 337–341 (2011). 21205640 10.1126/science.1198469 PMC3969237

136. Round JL The toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota Science 2011 332 974 977 21512004 10.1126/science.1206095 PMC3164325 Round, J. L. et al. The toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332 , 974–977 (2011). 21512004 10.1126/science.1206095 PMC3164325

137. Qian LJ Early-life gut microbial colonization shapes Th1/Th2 balance in asthma model in BALB/c mice BMC Microbiol. 2017 17 135 28623898 10.1186/s12866-017-1044-0 PMC5473985 Qian, L. J. et al. Early-life gut microbial colonization shapes Th1/Th2 balance in asthma model in BALB/c mice. BMC Microbiol. 17 , 135 (2017). 28623898 10.1186/s12866-017-1044-0 PMC5473985

138. Erturk-Hasdemir D Symbionts exploit complex signaling to educate the immune system Proc. Natl. Acad. Sci. USA 2019 116 26157 26166 31811024 10.1073/pnas.1915978116 PMC6936714 Erturk-Hasdemir, D. et al. Symbionts exploit complex signaling to educate the immune system. Proc. Natl. Acad. Sci. USA 116 , 26157–26166 (2019). 31811024 10.1073/pnas.1915978116 PMC6936714

139. Liu Q Sun Z Chen L Memory T cells: strategies for optimizing tumor immunotherapy Protein Cell 2020 11 549 564 32221812 10.1007/s13238-020-00707-9 PMC7381543 Liu, Q., Sun, Z. & Chen, L. Memory T cells: strategies for optimizing tumor immunotherapy. Protein Cell 11 , 549–564 (2020). 32221812 10.1007/s13238-020-00707-9 PMC7381543

140. Lu Y Gut microbiota influence immunotherapy responses: mechanisms and therapeutic strategies J. Hematol. Oncol. 2022 15 47 35488243 10.1186/s13045-022-01273-9 PMC9052532 Lu, Y. et al. Gut microbiota influence immunotherapy responses: mechanisms and therapeutic strategies. J. Hematol. Oncol. 15 , 47 (2022). 35488243 10.1186/s13045-022-01273-9 PMC9052532

141. Fujiwara D Systemic control of plasmacytoid dendritic cells by CD8+ T cells and commensal microbiota J. Immunol. 2008 180 5843 5852 18424703 10.4049/jimmunol.180.9.5843 PMC3439147 Fujiwara, D. et al. Systemic control of plasmacytoid dendritic cells by CD8+ T cells and commensal microbiota. J. Immunol. 180 , 5843–5852 (2008). 18424703 10.4049/jimmunol.180.9.5843 PMC3439147

142. Wei B Commensal microbiota and CD8+ T cells shape the formation of invariant NKT cells J. Immunol. 2010 184 1218 1226 20048124 10.4049/jimmunol.0902620 PMC3458428 Wei, B. et al. Commensal microbiota and CD8+ T cells shape the formation of invariant NKT cells. J. Immunol. 184 , 1218–1226 (2010). 20048124 10.4049/jimmunol.0902620 PMC3458428

143. Zhu R Gut microbiota: influence on carcinogenesis and modulation strategies by drug delivery systems to improve cancer therapy Adv. Sci. (Weinh.) 2021 8 2003542 34026439 10.1002/advs.202003542 PMC8132165 Zhu, R. et al. Gut microbiota: influence on carcinogenesis and modulation strategies by drug delivery systems to improve cancer therapy. Adv. Sci. (Weinh.) 8 , 2003542 (2021). 34026439 10.1002/advs.202003542 PMC8132165

144. Pei B Peng S Huang C Zhou F Bifidobacterium modulation of tumor immunotherapy and its mechanism Cancer Immunol. Immunother. 2024 73 94 38564002 10.1007/s00262-024-03665-x PMC10987355 Pei, B., Peng, S., Huang, C. & Zhou, F. Bifidobacterium modulation of tumor immunotherapy and its mechanism. Cancer Immunol. Immunother. 73 , 94 (2024). 38564002 10.1007/s00262-024-03665-x PMC10987355

145. Krautkramer KA Fan J Bäckhed F Gut microbial metabolites as multi-kingdom intermediates Nat. Rev. Microbiol. 2021 19 77 94 32968241 10.1038/s41579-020-0438-4 Krautkramer, K. A., Fan, J. & Bäckhed, F. Gut microbial metabolites as multi-kingdom intermediates. Nat. Rev. Microbiol. 19 , 77–94 (2021). 32968241 10.1038/s41579-020-0438-4

146. Yang W Cong Y Gut microbiota-derived metabolites in the regulation of host immune responses and immune-related inflammatory diseases Cell Mol. Immunol. 2021 18 866 877 33707689 10.1038/s41423-021-00661-4 PMC8115644 Yang, W. & Cong, Y. Gut microbiota-derived metabolites in the regulation of host immune responses and immune-related inflammatory diseases. Cell Mol. Immunol. 18 , 866–877 (2021). 33707689 10.1038/s41423-021-00661-4 PMC8115644

147. Zhang T Yang Y Liang Y Jiao X Zhao C Beneficial effect of intestinal fermentation of natural polysaccharides Nutrients 2018 10 1055 30096921 10.3390/nu10081055 PMC6116026 Zhang, T., Yang, Y., Liang, Y., Jiao, X. & Zhao, C. Beneficial effect of intestinal fermentation of natural polysaccharides. Nutrients 10 , 1055 (2018). 30096921 10.3390/nu10081055 PMC6116026

148. Viretta L Oldfield D Sali A Inflammatory bowel diseases and the efficacy of probiotics as functional foods Front Biosci. (Elite Ed.) 2024 16 13 38939911 10.31083/j.fbe1602013 Viretta, L., Oldfield, D. & Sali, A. Inflammatory bowel diseases and the efficacy of probiotics as functional foods. Front Biosci. (Elite Ed.) 16 , 13 (2024). 38939911 10.31083/j.fbe1602013

149. Sun J Butyrate as a promising therapeutic target in cancer: From pathogenesis to clinic Int J. Oncol. 2024 64 44 38426581 10.3892/ijo.2024.5632 PMC10919761 Sun, J. et al. Butyrate as a promising therapeutic target in cancer: From pathogenesis to clinic. Int J. Oncol. 64 , 44 (2024). 38426581 10.3892/ijo.2024.5632 PMC10919761

150. Gomes AP Altered propionate metabolism contributes to tumour progression and aggressiveness Nat. Metab. 2022 4 435 443 35361954 10.1038/s42255-022-00553-5 PMC9050834 Gomes, A. P. et al. Altered propionate metabolism contributes to tumour progression and aggressiveness. Nat. Metab. 4 , 435–443 (2022). 35361954 10.1038/s42255-022-00553-5 PMC9050834

151. Xue C Tryptophan metabolism in health and disease Cell Metab. 2023 35 1304 1326 37352864 10.1016/j.cmet.2023.06.004 Xue, C. et al. Tryptophan metabolism in health and disease. Cell Metab. 35 , 1304–1326 (2023). 37352864 10.1016/j.cmet.2023.06.004

152. Bender MJ Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment Cell 2023 186 1846 1862.e26 37028428 10.1016/j.cell.2023.03.011 PMC10148916 Bender, M. J. et al. Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment. Cell 186 , 1846–1862.e26 (2023). 37028428 10.1016/j.cell.2023.03.011 PMC10148916

153. Hezaveh K Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity Immunity 2022 55 324 340.e8 35139353 10.1016/j.immuni.2022.01.006 PMC8888129 Hezaveh, K. et al. Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity. Immunity 55 , 324–340.e8 (2022). 35139353 10.1016/j.immuni.2022.01.006 PMC8888129

154. Zhang L Inhibition of UBA6 by inosine augments tumour immunogenicity and responses Nat. Commun. 2022 13 5413 36109526 10.1038/s41467-022-33116-z PMC9478149 Zhang, L. et al. Inhibition of UBA6 by inosine augments tumour immunogenicity and responses. Nat. Commun. 13 , 5413 (2022). 36109526 10.1038/s41467-022-33116-z PMC9478149

155. Mager LF Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy Science 2020 369 1481 1489 32792462 10.1126/science.abc3421 Mager, L. F. et al. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy. Science 369 , 1481–1489 (2020). 32792462 10.1126/science.abc3421

156. An D Sphingolipids from a symbiotic microbe regulate homeostasis of host intestinal natural killer T cells Cell 2014 156 123 133 24439373 10.1016/j.cell.2013.11.042 PMC3909465 An, D. et al. Sphingolipids from a symbiotic microbe regulate homeostasis of host intestinal natural killer T cells. Cell 156 , 123–133 (2014). 24439373 10.1016/j.cell.2013.11.042 PMC3909465

157. Ogretmen B Sphingolipid metabolism in cancer signalling and therapy Nat. Rev. Cancer 2018 18 33 50 29147025 10.1038/nrc.2017.96 PMC5818153 Ogretmen, B. Sphingolipid metabolism in cancer signalling and therapy. Nat. Rev. Cancer 18 , 33–50 (2018). 29147025 10.1038/nrc.2017.96 PMC5818153

158. Lee M Lee SY Bae YS Functional roles of sphingolipids in immunity and their implication in disease Exp. Mol. Med. 2023 55 1110 1130 37258585 10.1038/s12276-023-01018-9 PMC10318102 Lee, M., Lee, S. Y. & Bae, Y. S. Functional roles of sphingolipids in immunity and their implication in disease. Exp. Mol. Med. 55 , 1110–1130 (2023). 37258585 10.1038/s12276-023-01018-9 PMC10318102

159. Johnson EL Sphingolipids produced by gut bacteria enter host metabolic pathways impacting ceramide levels Nat. Commun. 2020 11 2471 32424203 10.1038/s41467-020-16274-w PMC7235224 Johnson, E. L. et al. Sphingolipids produced by gut bacteria enter host metabolic pathways impacting ceramide levels. Nat. Commun. 11 , 2471 (2020). 32424203 10.1038/s41467-020-16274-w PMC7235224

160. Chakraborty P Pro-Survival Lipid Sphingosine-1-Phosphate Metabolically Programs T Cells to Limit Anti-tumor Activity Cell Rep. 2019 28 1879 1893.e7 31412253 10.1016/j.celrep.2019.07.044 PMC6889821 Chakraborty, P. et al. Pro-Survival Lipid Sphingosine-1-Phosphate Metabolically Programs T Cells to Limit Anti-tumor Activity. Cell Rep. 28 , 1879–1893.e7 (2019). 31412253 10.1016/j.celrep.2019.07.044 PMC6889821

161. Grüner N Mattner J Bile Acids and Microbiota: Multifaceted and Versatile Regulators of the Liver-Gut Axis Int J. Mol. Sci. 2021 22 1397 33573273 10.3390/ijms22031397 PMC7866539 Grüner, N. & Mattner, J. Bile Acids and Microbiota: Multifaceted and Versatile Regulators of the Liver-Gut Axis. Int J. Mol. Sci. 22 , 1397 (2021). 33573273 10.3390/ijms22031397 PMC7866539

162. Paik D Human gut bacteria produce TauEta17-modulating bile acid metabolites Nature 2022 603 907 912 35296854 10.1038/s41586-022-04480-z PMC9132548 Paik, D. et al. Human gut bacteria produce TauEta17-modulating bile acid metabolites. Nature 603 , 907–912 (2022). 35296854 10.1038/s41586-022-04480-z PMC9132548

163. Li W A bacterial bile acid metabolite modulates Treg activity through the nuclear hormone receptor NR4A1 Cell Host Microbe 2021 29 1366 1377.e9 34416161 10.1016/j.chom.2021.07.013 PMC9064000 Li, W. et al. A bacterial bile acid metabolite modulates Treg activity through the nuclear hormone receptor NR4A1. Cell Host Microbe 29 , 1366–1377.e9 (2021). 34416161 10.1016/j.chom.2021.07.013 PMC9064000

164. Režen T The role of bile acids in carcinogenesis Cell Mol. Life Sci. 2022 79 243 35429253 10.1007/s00018-022-04278-2 PMC9013344 Režen, T. et al. The role of bile acids in carcinogenesis. Cell Mol. Life Sci. 79 , 243 (2022). 35429253 10.1007/s00018-022-04278-2 PMC9013344

165. Yin Q Ni JJ Ying JE Potential mechanisms and targeting strategies of the gut microbiota in antitumor immunity and immunotherapy Immun. Inflamm. Dis. 2024 12 e1263 39031507 10.1002/iid3.1263 PMC11259004 Yin, Q., Ni, J. J. & Ying, J. E. Potential mechanisms and targeting strategies of the gut microbiota in antitumor immunity and immunotherapy. Immun. Inflamm. Dis. 12 , e1263 (2024). 39031507 10.1002/iid3.1263 PMC11259004

166. Uebanso T Shimohata T Mawatari K Takahashi A Functional Roles of B-Vitamins in the Gut and Gut Microbiome Mol. Nutr. Food Res 2020 64 e2000426 32761878 10.1002/mnfr.202000426 Uebanso, T., Shimohata, T., Mawatari, K. & Takahashi, A. Functional Roles of B-Vitamins in the Gut and Gut Microbiome. Mol. Nutr. Food Res 64 , e2000426 (2020). 32761878 10.1002/mnfr.202000426

167. Yang Y Dietary vitamin B3 supplementation induces the antitumor immunity against liver cancer via biased GPR109A signaling in myeloid cell Cell Rep. Med. 2024 5 101718 39293389 10.1016/j.xcrm.2024.101718 PMC11525019 Yang, Y. et al. Dietary vitamin B3 supplementation induces the antitumor immunity against liver cancer via biased GPR109A signaling in myeloid cell. Cell Rep. Med. 5 , 101718 (2024). 39293389 10.1016/j.xcrm.2024.101718 PMC11525019

168. Hossain KS Amarasena S Mayengbam S B Vitamins and Their Roles in Gut Health Microorganisms 2022 10 1168 35744686 10.3390/microorganisms10061168 PMC9227236 Hossain, K. S., Amarasena, S. & Mayengbam, S. B Vitamins and Their Roles in Gut Health. Microorganisms 10 , 1168 (2022). 35744686 10.3390/microorganisms10061168 PMC9227236

169. Sujol G Docquier A Boulahtouf A Castet-Nicolas A Cavaillès V Vitamin B6 and cancer: from clinical data to molecularly mechanisms Bull. Cancer 2011 98 1201 1208 22001823 10.1684/bdc.2011.1458 Sujol, G., Docquier, A., Boulahtouf, A., Castet-Nicolas, A. & Cavaillès, V. Vitamin B6 and cancer: from clinical data to molecularly mechanisms. Bull. Cancer 98 , 1201–1208 (2011). 22001823 10.1684/bdc.2011.1458

170. Daillere R Enterococcus hirae and Barnesiella intestinihominis facilitate cyclophosphamide-induced therapeutic immunomodulatory effects Immunity 2016 45 931 943 27717798 10.1016/j.immuni.2016.09.009 Daillere, R. et al. Enterococcus hirae and Barnesiella intestinihominis facilitate cyclophosphamide-induced therapeutic immunomodulatory effects. Immunity 45 , 931–943 (2016). 27717798 10.1016/j.immuni.2016.09.009

171. Lam KC Microbiota triggers STING-type I IFN-dependent monocyte reprogramming of the tumor microenvironment Cell 2021 184 5338 56.e21 34624222 10.1016/j.cell.2021.09.019 PMC8650838 Lam, K. C. et al. Microbiota triggers STING-type I IFN-dependent monocyte reprogramming of the tumor microenvironment. Cell 184 , 5338–56.e21 (2021). 34624222 10.1016/j.cell.2021.09.019 PMC8650838

172. Wang T Inosine is an alternative carbon source for CD8(+)-T-cell function under glucose restriction Nat. Metab. 2020 2 635 647 32694789 10.1038/s42255-020-0219-4 PMC7371628 Wang, T. et al. Inosine is an alternative carbon source for CD8(+)-T-cell function under glucose restriction. Nat. Metab. 2 , 635–647 (2020). 32694789 10.1038/s42255-020-0219-4 PMC7371628

173. Fluckiger A Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage Science 2020 369 936 942 32820119 10.1126/science.aax0701 Fluckiger, A. et al. Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage. Science 369 , 936–942 (2020). 32820119 10.1126/science.aax0701

174. Bessell CA Commensal bacteria stimulate antitumor responses via T cell cross-reactivity JCI insight 2020 5 e135597 32324171 10.1172/jci.insight.135597 PMC7205429 Bessell, C. A. et al. Commensal bacteria stimulate antitumor responses via T cell cross-reactivity. JCI insight 5 , e135597 (2020). 32324171 10.1172/jci.insight.135597 PMC7205429

175. Naghavian R Microbial peptides activate tumour-infiltrating lymphocytes in glioblastoma Nature 2023 617 807 817 37198490 10.1038/s41586-023-06081-w PMC10208956 Naghavian, R. et al. Microbial peptides activate tumour-infiltrating lymphocytes in glioblastoma. Nature 617 , 807–817 (2023). 37198490 10.1038/s41586-023-06081-w PMC10208956

176. Martins F Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance Nat. Rev. Clin. Oncol. 2019 16 563 580 31092901 10.1038/s41571-019-0218-0 Martins, F. et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat. Rev. Clin. Oncol. 16 , 563–580 (2019). 31092901 10.1038/s41571-019-0218-0

177. Baxi S Yang A Gennarelli RL Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis BMJ 2018 360 k793 29540345 10.1136/bmj.k793 PMC5851471 Baxi, S., Yang, A. & Gennarelli, R. L. Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis. BMJ 360 , k793 (2018). 29540345 10.1136/bmj.k793 PMC5851471

178. Wang Z Guo Y Han W Current status and perspectives of chimeric antigen receptor modified T cells for cancer treatment Protein Cell 2017 8 896 925 28466386 10.1007/s13238-017-0400-z PMC5712290 Wang, Z., Guo, Y. & Han, W. Current status and perspectives of chimeric antigen receptor modified T cells for cancer treatment. Protein Cell 8 , 896–925 (2017). 28466386 10.1007/s13238-017-0400-z PMC5712290

179. Liu Y Intestinal microbiota and its effect on vaccine-induced immune amplification and tolerance Vaccines (Basel) 2024 12 868 39203994 10.3390/vaccines12080868 PMC11359036 Liu, Y. et al. Intestinal microbiota and its effect on vaccine-induced immune amplification and tolerance. Vaccines (Basel) 12 , 868 (2024). 39203994 10.3390/vaccines12080868 PMC11359036

180. Zheng Y Effect of a probiotic formula on gastrointestinal health, immune responses and metabolic health in adults with functional constipation or functional diarrhea Front. Nutr. 2023 10 1196625 37497057 10.3389/fnut.2023.1196625 PMC10368241 Zheng, Y. et al. Effect of a probiotic formula on gastrointestinal health, immune responses and metabolic health in adults with functional constipation or functional diarrhea. Front. Nutr. 10 , 1196625 (2023). 37497057 10.3389/fnut.2023.1196625 PMC10368241

181. Usyk M Bacteroides vulgatus and Bacteroides dorei predict immune-related adverse events in immune checkpoint blockade treatment of metastatic melanoma Genome Med. 2021 13 160 34641962 10.1186/s13073-021-00974-z PMC8513370 Usyk, M. et al. Bacteroides vulgatus and Bacteroides dorei predict immune-related adverse events in immune checkpoint blockade treatment of metastatic melanoma. Genome Med. 13 , 160 (2021). 34641962 10.1186/s13073-021-00974-z PMC8513370

182. Wang Y Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis Nat. Med. 2018 24 1804 1808 30420754 10.1038/s41591-018-0238-9 PMC6322556 Wang, Y. et al. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat. Med. 24 , 1804–1808 (2018). 30420754 10.1038/s41591-018-0238-9 PMC6322556

183. Blake SJ The immunotoxicity, but not anti-tumor efficacy, of anti-CD40 and anti-CD137 immunotherapies is dependent on the gut microbiota Cell Rep. Med. 2021 2 100464 35028606 10.1016/j.xcrm.2021.100464 PMC8714857 Blake, S. J. et al. The immunotoxicity, but not anti-tumor efficacy, of anti-CD40 and anti-CD137 immunotherapies is dependent on the gut microbiota. Cell Rep. Med. 2 , 100464 (2021). 35028606 10.1016/j.xcrm.2021.100464 PMC8714857

184. Chaput N Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab Ann. Oncol. 2017 28 1368 1379 28368458 10.1093/annonc/mdx108 Chaput, N. et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann. Oncol. 28 , 1368–1379 (2017). 28368458 10.1093/annonc/mdx108

185. Nejman D The human tumor microbiome is composed of tumor type-specific intracellular bacteria Science 2020 368 973 980 32467386 10.1126/science.aay9189 PMC7757858 Nejman, D. et al. The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science 368 , 973–980 (2020). 32467386 10.1126/science.aay9189 PMC7757858

186. Choi Y, et al. Immune checkpoint blockade induces gut microbiota translocation that augments extraintestinal antitumor immunity. Sci Immunol. 8, eabo2003 (2023). 10.1126/sciimmunol.abo2003 PMC10080670 36867675

187. Ferrari V Rescigno M The intratumoral microbiota: friend or foe? Trends Cancer 2023 9 472 479 37061408 10.1016/j.trecan.2023.03.005 Ferrari, V. & Rescigno, M. The intratumoral microbiota: friend or foe?. Trends Cancer 9 , 472–479 (2023). 37061408 10.1016/j.trecan.2023.03.005

188. Xu J Research progress on the impact of intratumoral microbiota on the immune microenvironment of malignant tumors and its role in immunotherapy Front. Immunol. 2024 15 1389446 39034996 10.3389/fimmu.2024.1389446 PMC11257860 Xu, J. et al. Research progress on the impact of intratumoral microbiota on the immune microenvironment of malignant tumors and its role in immunotherapy. Front. Immunol. 15 , 1389446 (2024). 39034996 10.3389/fimmu.2024.1389446 PMC11257860

189. Zhang T Intratumoral Fusobacterium nucleatum recruits tumor-associated neutrophils to promote gastric cancer progression and immune evasion Cancer Res. 2025 85 1819 1841 39992708 10.1158/0008-5472.CAN-24-2580 PMC12079103 Zhang, T. et al. Intratumoral Fusobacterium nucleatum recruits tumor-associated neutrophils to promote gastric cancer progression and immune evasion. Cancer Res. 85 , 1819–1841 (2025). 2025. 39992708 10.1158/0008-5472.CAN-24-2580 PMC12079103

190. Gur C Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack Immunity 2015 42 344 355 25680274 10.1016/j.immuni.2015.01.010 PMC4361732 Gur, C. et al. Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. Immunity 42 , 344–355 (2015). 25680274 10.1016/j.immuni.2015.01.010 PMC4361732

191. Chen S Fusobacterium nucleatum reduces METTL3-mediated m6A modification and contributes to colorectal cancer metastasis Nat. Commun. 2022 13 1248 35273176 10.1038/s41467-022-28913-5 PMC8913623 Chen, S. et al. Fusobacterium nucleatum reduces METTL3-mediated m6A modification and contributes to colorectal cancer metastasis. Nat. Commun. 13 , 1248 (2022). 35273176 10.1038/s41467-022-28913-5 PMC8913623

192. Ma Y Intratumor microbiome-derived butyrate promotes lung cancer metastasis Cell Rep. Med. 2024 5 101488 38565146 10.1016/j.xcrm.2024.101488 PMC11031379 Ma, Y. et al. Intratumor microbiome-derived butyrate promotes lung cancer metastasis. Cell Rep. Med. 5 , 101488 (2024). 38565146 10.1016/j.xcrm.2024.101488 PMC11031379

193. Miao BP Inhibition of squamous cancer growth in a mouse model by Staphylococcal enterotoxin B-triggered Th9 cell expansion Cell Mol. Immunol. 2017 14 371 379 26388239 10.1038/cmi.2015.88 PMC5380942 Miao, B. P. et al. Inhibition of squamous cancer growth in a mouse model by Staphylococcal enterotoxin B-triggered Th9 cell expansion. Cell Mol. Immunol. 14 , 371–379 (2017). 26388239 10.1038/cmi.2015.88 PMC5380942

194. Sun J Chen F Wu G Potential effects of gut microbiota on host cancers: focus on immunity, DNA damage, cellular pathways, and anticancer therapy ISME J. 2023 17 1535 1551 37553473 10.1038/s41396-023-01483-0 PMC10504269 Sun, J., Chen, F. & Wu, G. Potential effects of gut microbiota on host cancers: focus on immunity, DNA damage, cellular pathways, and anticancer therapy. ISME J. 17 , 1535–1551 (2023). 37553473 10.1038/s41396-023-01483-0 PMC10504269

195. Wilson RM The human gut bacterial genotoxin colibactin alkylates DNA Science 2019 363 eaar7785 30765538 10.1126/science.aar7785 PMC6407708 Wilson, R. M. et al. The human gut bacterial genotoxin colibactin alkylates DNA. Science 363 , eaar7785 (2019). 30765538 10.1126/science.aar7785 PMC6407708

196. Goodwin AC Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis Proc. Natl Acad. Sci. USA 2011 108 15354 15359 21876161 10.1073/pnas.1010203108 PMC3174648 Goodwin, A. C. et al. Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis. Proc. Natl Acad. Sci. USA 108 , 15354–15359 (2011). 21876161 10.1073/pnas.1010203108 PMC3174648

197. Geller LT Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine Science 2017 357 1156 1160 28912244 10.1126/science.aah5043 PMC5727343 Geller, L. T. et al. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science 357 , 1156–1160 (2017). 28912244 10.1126/science.aah5043 PMC5727343

198. Wyatt M Greathouse KL Targeting Dietary and Microbial Tryptophan-Indole Metabolism as Therapeutic Approaches to Colon Cancer Nutrients 2021 13 1189 33916690 10.3390/nu13041189 PMC8066279 Wyatt, M. & Greathouse, K. L. Targeting Dietary and Microbial Tryptophan-Indole Metabolism as Therapeutic Approaches to Colon Cancer. Nutrients 13 , 1189 (2021). 33916690 10.3390/nu13041189 PMC8066279

199. Overacre-Delgoffe AE Microbiota-specific T follicular helper cells drive tertiary lymphoid structures and anti-tumor immunity against colorectal cancer Immunity 2021 54 2812 2824.e4 34861182 10.1016/j.immuni.2021.11.003 PMC8865366 Overacre-Delgoffe, A. E. et al. Microbiota-specific T follicular helper cells drive tertiary lymphoid structures and anti-tumor immunity against colorectal cancer. Immunity 54 , 2812–2824.e4 (2021). 34861182 10.1016/j.immuni.2021.11.003 PMC8865366

200. Yang L Li A Wang Y Zhang Y Intratumoral microbiota: roles in cancer initiation, development and therapeutic efficacy Signal Transduct. Target Ther. 2023 8 35 36646684 10.1038/s41392-022-01304-4 PMC9842669 Yang, L., Li, A., Wang, Y. & Zhang, Y. Intratumoral microbiota: roles in cancer initiation, development and therapeutic efficacy. Signal Transduct. Target Ther. 8 , 35 (2023). 36646684 10.1038/s41392-022-01304-4 PMC9842669

201. Shi Y Intra-tumoral accumulation of gut microbiota facilitates CD47-based immunotherapy via STING signaling J. Exp. Med. 2020 217 e20192282 32142585 10.1084/jem.20192282 PMC7201921 Shi, Y. et al. Intra-tumoral accumulation of gut microbiota facilitates CD47-based immunotherapy via STING signaling. J. Exp. Med. 217 , e20192282 (2020). 32142585 10.1084/jem.20192282 PMC7201921

202. Dwivedi M Kumar P Laddha NC Kemp EH Induction of regulatory T cells: A role for probiotics and prebiotics to suppress autoimmunity Autoimmun. Rev. 2016 15 379 392 26774011 10.1016/j.autrev.2016.01.002 Dwivedi, M., Kumar, P., Laddha, N. C. & Kemp, E. H. Induction of regulatory T cells: A role for probiotics and prebiotics to suppress autoimmunity. Autoimmun. Rev. 15 , 379–392 (2016). 26774011 10.1016/j.autrev.2016.01.002

203. Han S d-lactate modulates M2 tumor-associated macrophages and remodels immunosuppressive tumor microenvironment for hepatocellular carcinoma Sci. Adv. 2023 9 eadg2697 37467325 10.1126/sciadv.adg2697 PMC10355835 Han, S. et al. d-lactate modulates M2 tumor-associated macrophages and remodels immunosuppressive tumor microenvironment for hepatocellular carcinoma. Sci. Adv. 9 , eadg2697 (2023). 37467325 10.1126/sciadv.adg2697 PMC10355835

204. Takeuchi T Nakanishi Y Ohno H Microbial metabolites and gut immunology Annu. Rev. Immunol. 2024 42 153 178 38941602 10.1146/annurev-immunol-090222-102035 Takeuchi, T., Nakanishi, Y. & Ohno, H. Microbial metabolites and gut immunology. Annu. Rev. Immunol. 42 , 153–178 (2024). 38941602 10.1146/annurev-immunol-090222-102035

205. Domzaridou E The impact of oral antibiotics prior to cancer diagnosis on overall patient survival: findings from an english population-based cohort study Curr. Oncol. 2023 30 8434 8443 37754529 10.3390/curroncol30090614 PMC10528751 Domzaridou, E. et al. The impact of oral antibiotics prior to cancer diagnosis on overall patient survival: findings from an english population-based cohort study. Curr. Oncol. 30 , 8434–8443 (2023). 37754529 10.3390/curroncol30090614 PMC10528751

206. Kim H The effect of antibiotics on the clinical outcomes of patients with solid cancers undergoing immune checkpoint inhibitor treatment: a retrospective study BMC Cancer 2019 19 1100 31718585 10.1186/s12885-019-6267-z PMC6852740 Kim, H. et al. The effect of antibiotics on the clinical outcomes of patients with solid cancers undergoing immune checkpoint inhibitor treatment: a retrospective study. BMC Cancer 19 , 1100 (2019). 31718585 10.1186/s12885-019-6267-z PMC6852740

207. Huang XZ Antibiotic use and the efficacy of immune checkpoint inhibitors in cancer patients: a pooled analysis of 2740 cancer patients Oncoimmunology 2019 8 e1665973 31741763 10.1080/2162402X.2019.1665973 PMC6844307 Huang, X. Z. et al. Antibiotic use and the efficacy of immune checkpoint inhibitors in cancer patients: a pooled analysis of 2740 cancer patients. Oncoimmunology 8 , e1665973 (2019). 31741763 10.1080/2162402X.2019.1665973 PMC6844307

208. Wilson BE The effect of antibiotics on clinical outcomes in immune-checkpoint blockade: a systematic review and meta-analysis of observational studies Cancer Immunol. Immunother. 2020 69 343 354 31865400 10.1007/s00262-019-02453-2 PMC11027824 Wilson, B. E. et al. The effect of antibiotics on clinical outcomes in immune-checkpoint blockade: a systematic review and meta-analysis of observational studies. Cancer Immunol. Immunother. 69 , 343–354 (2020). 31865400 10.1007/s00262-019-02453-2 PMC11027824

209. Yang M Antibiotic administration shortly before or after immunotherapy initiation is correlated with poor prognosis in solid cancer patients: an up-to-date systematic review and meta-analysis Int. Immunopharmacol. 2020 88 106876 32799113 10.1016/j.intimp.2020.106876 Yang, M. et al. Antibiotic administration shortly before or after immunotherapy initiation is correlated with poor prognosis in solid cancer patients: an up-to-date systematic review and meta-analysis. Int. Immunopharmacol. 88 , 106876 (2020). 32799113 10.1016/j.intimp.2020.106876

210. Cren PY Is the survival of patients treated with ipilimumab affected by antibiotics? An analysis of 1585 patients from the French National hospital discharge summary database (PMSI) Oncoimmunology 2020 9 1846914 33299658 10.1080/2162402X.2020.1846914 PMC7714497 Cren, P. Y. et al. Is the survival of patients treated with ipilimumab affected by antibiotics? An analysis of 1585 patients from the French National hospital discharge summary database (PMSI). Oncoimmunology 9 , 1846914 (2020). 33299658 10.1080/2162402X.2020.1846914 PMC7714497

211. Kulkarni AA Comparative analysis of antibiotic exposure association with clinical outcomes of chemotherapy versus immunotherapy across three tumour types ESMO Open 2020 5 e000803 32900789 10.1136/esmoopen-2020-000803 PMC7477978 Kulkarni, A. A. et al. Comparative analysis of antibiotic exposure association with clinical outcomes of chemotherapy versus immunotherapy across three tumour types. ESMO Open 5 , e000803 (2020). 32900789 10.1136/esmoopen-2020-000803 PMC7477978

212. Lalani AA Effect of antibiotic use on outcomes with systemic therapies in metastatic renal cell carcinoma Eur. Urol. Oncol. 2020 3 372 381 31562048 10.1016/j.euo.2019.09.001 PMC9163676 Lalani, A. A. et al. Effect of antibiotic use on outcomes with systemic therapies in metastatic renal cell carcinoma. Eur. Urol. Oncol. 3 , 372–381 (2020). 31562048 10.1016/j.euo.2019.09.001 PMC9163676

213. Fessas P Early antibiotic exposure is not detrimental to therapeutic effect from immunotherapy in hepatocellular carcinoma Liver Cancer 2021 10 583 592 34950181 10.1159/000519108 PMC8647090 Fessas, P. et al. Early antibiotic exposure is not detrimental to therapeutic effect from immunotherapy in hepatocellular carcinoma. Liver Cancer 10 , 583–592 (2021). 34950181 10.1159/000519108 PMC8647090

214. Kostine M Baseline co-medications may alter the anti-tumoural effect of checkpoint inhibitors as well as the risk of immune-related adverse events Eur. J. Cancer 2021 157 474 484 34649118 10.1016/j.ejca.2021.08.036 Kostine, M. et al. Baseline co-medications may alter the anti-tumoural effect of checkpoint inhibitors as well as the risk of immune-related adverse events. Eur. J. Cancer 157 , 474–484 (2021). 34649118 10.1016/j.ejca.2021.08.036

215. Wu Q Liu J Wu S Xie X The impact of antibiotics on efficacy of immune checkpoint inhibitors in malignancies: a study based on 44 cohorts Int Immunopharmacol. 2021 92 107303 33465728 10.1016/j.intimp.2020.107303 Wu, Q., Liu, J., Wu, S. & Xie, X. The impact of antibiotics on efficacy of immune checkpoint inhibitors in malignancies: a study based on 44 cohorts. Int Immunopharmacol. 92 , 107303 (2021). 33465728 10.1016/j.intimp.2020.107303

216. Mohiuddin JJ Association of antibiotic exposure with survival and toxicity in patients with melanoma receiving immunotherapy J. Natl Cancer Inst. 2021 113 162 170 32294209 10.1093/jnci/djaa057 PMC7850522 Mohiuddin, J. J. et al. Association of antibiotic exposure with survival and toxicity in patients with melanoma receiving immunotherapy. J. Natl Cancer Inst. 113 , 162–170 (2021). 32294209 10.1093/jnci/djaa057 PMC7850522

217. Jing Y Association of antibiotic treatment with immune-related adverse events in patients with cancer receiving immunotherapy J. Immunother. Cancer 2022 10 e003779 35058327 10.1136/jitc-2021-003779 PMC8772460 Jing, Y. et al. Association of antibiotic treatment with immune-related adverse events in patients with cancer receiving immunotherapy. J. Immunother. Cancer 10 , e003779 (2022). 35058327 10.1136/jitc-2021-003779 PMC8772460

218. Nyein AF Effect of prior antibiotic or chemotherapy treatment on immunotherapy response in non-small cell lung cancer BMC Cancer 2022 22 101 35073876 10.1186/s12885-022-09210-2 PMC8787935 Nyein, A. F. et al. Effect of prior antibiotic or chemotherapy treatment on immunotherapy response in non-small cell lung cancer. BMC Cancer 22 , 101 (2022). 35073876 10.1186/s12885-022-09210-2 PMC8787935

219. Zhao L Association of blood biochemical indexes and antibiotic exposure with severe immune-related adverse events in patients with advanced cancers receiving PD-1 inhibitors J. Immunother. 2022 45 210 216 35250004 10.1097/CJI.0000000000000415 PMC8986630 Zhao, L. et al. Association of blood biochemical indexes and antibiotic exposure with severe immune-related adverse events in patients with advanced cancers receiving PD-1 inhibitors. J. Immunother. 45 , 210–216 (2022). 35250004 10.1097/CJI.0000000000000415 PMC8986630

220. Poizeau F The association between antibiotic use and outcome among metastatic melanoma patients receiving immunotherapy J. Natl Cancer Inst. 2022 114 686 694 35253890 10.1093/jnci/djac019 PMC9086805 Poizeau, F. et al. The association between antibiotic use and outcome among metastatic melanoma patients receiving immunotherapy. J. Natl Cancer Inst. 114 , 686–694 (2022). 35253890 10.1093/jnci/djac019 PMC9086805

221. Pressner S Heiland M Preissner R Wirth M Wollenberg B Antibiotics significantly decrease the survival of head and neck carcinoma patients with immunotherapy: a real-world analysis of more than 3000 cases Cancers (Basel) 2023 15 2342 37190270 10.3390/cancers15082342 PMC10136869 Pressner, S., Heiland, M., Preissner, R., Wirth, M. & Wollenberg, B. Antibiotics significantly decrease the survival of head and neck carcinoma patients with immunotherapy: a real-world analysis of more than 3000 cases. Cancers (Basel) 15 , 2342 (2023). 37190270 10.3390/cancers15082342 PMC10136869

222. Pinato DJ Association between antibiotics and adverse oncological outcomes in patients receiving targeted or immune-based therapy for hepatocellular carcinoma JHEP Rep. 2023 5 100747 37197442 10.1016/j.jhepr.2023.100747 PMC10183666 Pinato, D. J. et al. Association between antibiotics and adverse oncological outcomes in patients receiving targeted or immune-based therapy for hepatocellular carcinoma. JHEP Rep. 5 , 100747 (2023). 37197442 10.1016/j.jhepr.2023.100747 PMC10183666

223. Kulkarini AA Association of antibiotic exposure with residual cancer burden in HER2-negative early stage breast cancer NPJ Breast Cancer 2024 10 24 38531875 10.1038/s41523-024-00630-w PMC10966095 Kulkarini, A. A. et al. Association of antibiotic exposure with residual cancer burden in HER2-negative early stage breast cancer. NPJ Breast Cancer 10 , 24 (2024). 38531875 10.1038/s41523-024-00630-w PMC10966095

224. Glitza IC Randomized placebo-controlled, biomarker-stratified phase ib microbiome modulation in melanoma: impact of antibiotic preconditioning on microbiome and immunity Cancer Discov. 2024 14 1161 1175 38588588 10.1158/2159-8290.CD-24-0066 PMC11215408 Glitza, I. C. et al. Randomized placebo-controlled, biomarker-stratified phase ib microbiome modulation in melanoma: impact of antibiotic preconditioning on microbiome and immunity. Cancer Discov. 14 , 1161–1175 (2024). 38588588 10.1158/2159-8290.CD-24-0066 PMC11215408

225. Elkrief A Antibiotics are associated with worse outcomes in lung cancer patients treated with chemotherapy and immunotherapy NPJ Precis Oncol. 2024 8 143 39014160 10.1038/s41698-024-00630-w PMC11252311 Elkrief, A. et al. Antibiotics are associated with worse outcomes in lung cancer patients treated with chemotherapy and immunotherapy. NPJ Precis Oncol. 8 , 143 (2024). 39014160 10.1038/s41698-024-00630-w PMC11252311

226. Prasad, R. et al. Antibiotic-induced loss of gut microbiome metabolic output correlates with clinical responses to CAR T-cell therapy. Blood 145 , 823–839 (2024). 10.1182/blood.2024025366 39441941

227. Takada K Takamori S Shimokawa M Pinato D Cortellini A Prior antibiotics, proton pump inhibitors, and probiotics in patients with extensive stage small cell lung cancer treated with immune checkpoint blockade: a post-hoc analysis of the phase I/III IMpower 133 trial Int J. Cancer 2025 156 914 919 39501485 10.1002/ijc.35249 Takada, K., Takamori, S., Shimokawa, M., Pinato, D. & Cortellini, A. Prior antibiotics, proton pump inhibitors, and probiotics in patients with extensive stage small cell lung cancer treated with immune checkpoint blockade: a post-hoc analysis of the phase I/III IMpower 133 trial. Int J. Cancer 156 , 914–919 (2025). 39501485 10.1002/ijc.35249

228. Bonnefin C Antibiotics use decreases survival in cutaneous squamous cell carcinoma patients receiving immune checkpoint inhibitors Eur. J. Cancer 2025 217 115223 39874910 10.1016/j.ejca.2025.115223 Bonnefin, C. et al. Antibiotics use decreases survival in cutaneous squamous cell carcinoma patients receiving immune checkpoint inhibitors. Eur. J. Cancer 217 , 115223 (2025). 39874910 10.1016/j.ejca.2025.115223

229. Cheng M Microbiota modulate tumoral immune surveillance in lung through a γδT17 immune cell-dependent mechanism Cancer Res. 2014 74 4030 4041 24947042 10.1158/0008-5472.CAN-13-2462 Cheng, M. et al. Microbiota modulate tumoral immune surveillance in lung through a γδT17 immune cell-dependent mechanism. Cancer Res. 74 , 4030–4041 (2014). 24947042 10.1158/0008-5472.CAN-13-2462

230. Derosa Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer Ann. Oncol. 2018 29 1437 1444 29617710 10.1093/annonc/mdy103 PMC6354674 Derosa et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann. Oncol. 29 , 1437–1444 (2018). 29617710 10.1093/annonc/mdy103 PMC6354674

231. Chalabi M Efficacy of chemotherapy and atezolizumab in patients with non-small-cell lung cancer receiving antibiotics and proton pump inhibitors: pooled post hoc analyses of the OAK and POPLAR trials Ann. Oncol. 2020 31 525 531 32115349 10.1016/j.annonc.2020.01.006 Chalabi, M. et al. Efficacy of chemotherapy and atezolizumab in patients with non-small-cell lung cancer receiving antibiotics and proton pump inhibitors: pooled post hoc analyses of the OAK and POPLAR trials. Ann. Oncol. 31 , 525–531 (2020). 32115349 10.1016/j.annonc.2020.01.006

232. Palleja A Recovery of gut microbiota of healthy adults following antibiotic exposure Nat. Microbiol. 2018 3 1255 1265 30349083 10.1038/s41564-018-0257-9 Palleja, A. et al. Recovery of gut microbiota of healthy adults following antibiotic exposure. Nat. Microbiol. 3 , 1255–1265 (2018). 30349083 10.1038/s41564-018-0257-9

233. Ahmed J Use of broad-spectrum antibiotics impacts outcome in patients treated with immune checkpoint inhibitors Oncoimmunology 2018 7 e1507670 30377571 10.1080/2162402X.2018.1507670 PMC6205076 Ahmed, J. et al. Use of broad-spectrum antibiotics impacts outcome in patients treated with immune checkpoint inhibitors. Oncoimmunology 7 , e1507670 (2018). 30377571 10.1080/2162402X.2018.1507670 PMC6205076

234. Cai J Sun L Gonzalez FJ Gut microbiota-derived bile acids in intestinal immunity, inflammation, and tumorigenesis Cell Host Microbe 2022 30 289 300 35271802 10.1016/j.chom.2022.02.004 PMC8923532 Cai, J., Sun, L. & Gonzalez, F. J. Gut microbiota-derived bile acids in intestinal immunity, inflammation, and tumorigenesis. Cell Host Microbe 30 , 289–300 (2022). 35271802 10.1016/j.chom.2022.02.004 PMC8923532

235. Pernigoni N Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis Science 2021 374 216 224 34618582 10.1126/science.abf8403 Pernigoni, N. et al. Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis. Science 374 , 216–224 (2021). 34618582 10.1126/science.abf8403

236. Terrisse S Immune system and intestinal microbiota determine efficacy of androgen deprivation therapy against prostate cancer J. Immunother. Cancer 2022 10 e004191 35296557 10.1136/jitc-2021-004191 PMC8928383 Terrisse, S. et al. Immune system and intestinal microbiota determine efficacy of androgen deprivation therapy against prostate cancer. J. Immunother. Cancer 10 , e004191 (2022). 35296557 10.1136/jitc-2021-004191 PMC8928383

237. Ravà M Therapeutic synergy between tigecycline and venetoclax in a preclinical model of MYC/BCL2 double-hit B cell lymphoma Sci. Transl. Med. 2018 10 eaan8723 29386360 10.1126/scitranslmed.aan8723 Ravà, M. et al. Therapeutic synergy between tigecycline and venetoclax in a preclinical model of MYC/BCL2 double-hit B cell lymphoma. Sci. Transl. Med. 10 , eaan8723 (2018). 29386360 10.1126/scitranslmed.aan8723

238. Pushalkar S The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression Cancer Discov. 2018 8 403 416 29567829 10.1158/2159-8290.CD-17-1134 PMC6225783 Pushalkar, S. et al. The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discov. 8 , 403–416 (2018). 29567829 10.1158/2159-8290.CD-17-1134 PMC6225783

239. Sethi V Vitiello GA Saxena D Miller G Dudeja V The role of the microbiome in immunologic development and its implication for pancreatic cancer immunotherapy Gastroenterology 2019 156 2097 2115.e2 30768986 10.1053/j.gastro.2018.12.045 Sethi, V., Vitiello, G. A., Saxena, D., Miller, G. & Dudeja, V. The role of the microbiome in immunologic development and its implication for pancreatic cancer immunotherapy. Gastroenterology 156 , 2097–2115.e2 (2019). 30768986 10.1053/j.gastro.2018.12.045

240. Vitiello GA Cohen DJ Miller G Harnessing the microbiome for pancreatic cancer immunotherapy Trends Cancer 2019 5 670 676 31735286 10.1016/j.trecan.2019.10.005 Vitiello, G. A., Cohen, D. J. & Miller, G. Harnessing the microbiome for pancreatic cancer immunotherapy. Trends Cancer 5 , 670–676 (2019). 2019. 31735286 10.1016/j.trecan.2019.10.005

241. Bertocchi A Gut vascular barrier impairment leads to intestinal bacteria dissemination and colorectal cancer metastasis to liver Cancer Cell 2021 39 708 724.e11 33798472 10.1016/j.ccell.2021.03.004 Bertocchi, A. et al. Gut vascular barrier impairment leads to intestinal bacteria dissemination and colorectal cancer metastasis to liver. Cancer Cell 39 , 708–724.e11 (2021). 33798472 10.1016/j.ccell.2021.03.004

242. Schwan A Sjölin S Trottestam U Aronsson B Relapsing Clostridium difficile enterocolitis cured by rectal infusion of normal faeces Scand. J. Infect. Dis. 1984 16 211 215 6740251 10.3109/00365548409087145 Schwan, A., Sjölin, S., Trottestam, U. & Aronsson, B. Relapsing Clostridium difficile enterocolitis cured by rectal infusion of normal faeces. Scand. J. Infect. Dis. 16 , 211–215 (1984). 6740251 10.3109/00365548409087145

243. Pai N Popov J Hill L Hartung E Protocol for a double-blind, randomised, placebo-controlled pilot study for assessing the feasibility and efficacy of faecal microbiota transplant in a paediatric Crohn’s disease population: PediCRaFT Trial BMJ Open 2019 9 e030120 31784432 10.1136/bmjopen-2019-030120 PMC6924772 Pai, N., Popov, J., Hill, L. & Hartung, E. Protocol for a double-blind, randomised, placebo-controlled pilot study for assessing the feasibility and efficacy of faecal microbiota transplant in a paediatric Crohn’s disease population: PediCRaFT Trial. BMJ Open 9 , e030120 (2019). 31784432 10.1136/bmjopen-2019-030120 PMC6924772

244. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/ NCT06218602 (Accessed 15 February 2025).

245. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03353402 (Accessed 15 February 2025).

246. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03772899 (Accessed 15 February 2025).

247. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT05251389 (Accessed 15 February 2025).

248. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03341143 (Accessed 15 February 2025).

249. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04577729 (Accessed 15 February 2025).

250. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT06623461 (Accessed 15 February 2025).

251. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04521075 (Accessed 15 February 2025).

252. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04951583 (Accessed 15 February 2025).

253. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT05008861 (Accessed 15 February 2025).

254. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT06403111 (Accessed 15 February 2025).

255. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05502913 (Accessed 15 February 2025).

256. US National Library of MediciAccessed 15ne. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04924374 (Accessed 15 February 2025).

257. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04056026 (Accessed 15 February 2025).

258. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT06486220 (Accessed 15 February 2025).

259. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05750030 (Accessed 15 February 2025).

260. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05690048 Accessed 15 February 2025).

261. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT06405113 (Accessed 15 February 2025).

262. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04130763 (Accessed 15 February 2025).

263. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04038619 (Accessed 15 February 2025).

264. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04729322 (Accessed 15 February 2025).

265. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT05279677 (Accessed 15 February 2025).

266. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04163289 (Accessed 15 February 2025).

267. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04038619 (Accessed 15 February 2025).

268. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04758507 (Accessed 15 February 2025).

269. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04116775 (Accessed 15 February 2025).

270. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04883762 (Accessed 15 February 2025).

271. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04521075 (Accessed 15 February 2025).

272. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT05286294 (Accessed 15 February 2025).

273. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03819296 (Accessed 15 February 2025).

274. Chinese Clinical Trial Register. https://www.chictr.org.cn/historyversionpub.aspx?regno=ChiCTR2100042292 (Accessed 15 February 2025).

275. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05273255 (Accessed 15 February 2025).

276. Schluter J The gut microbiota is associated with immune cell dynamics in humans Nature 2020 588 303 307 33239790 10.1038/s41586-020-2971-8 PMC7725892 Schluter, J. et al. The gut microbiota is associated with immune cell dynamics in humans. Nature 588 , 303–307 (2020). 33239790 10.1038/s41586-020-2971-8 PMC7725892

277. Zhao Y Safety and efficacy of fecal microbiota transplantation for grade IV steroid refractory GI-GvHD patients: interim results from FMT2017002 trial Front Immunol. 2021 12 678476 34220825 10.3389/fimmu.2021.678476 PMC8248496 Zhao, Y. et al. Safety and efficacy of fecal microbiota transplantation for grade IV steroid refractory GI-GvHD patients: interim results from FMT2017002 trial. Front Immunol. 12 , 678476 (2021). 34220825 10.3389/fimmu.2021.678476 PMC8248496

278. Halesy TM Microbiome alteration via fecal microbiota transplantation is effective for refractory immune checkpoint inhibitor-induced colitis Sci. Transl. Med. 2023 15 eabq4006 37315113 10.1126/scitranslmed.abq4006 PMC10759507 Halesy, T. M. et al. Microbiome alteration via fecal microbiota transplantation is effective for refractory immune checkpoint inhibitor-induced colitis. Sci. Transl. Med. 15 , eabq4006 (2023). 37315113 10.1126/scitranslmed.abq4006 PMC10759507

279. Helmink BA Khan MAW Hermann A Gopalakrishnan V Wargo JA The microbiome, cancer, and cancer therapy Nat. Med. 2019 25 377 88 30842679 10.1038/s41591-019-0377-7 Helmink, B. A., Khan, M. A. W., Hermann, A., Gopalakrishnan, V. & Wargo, J. A. The microbiome, cancer, and cancer therapy. Nat. Med. 25 , 377–88 (2019). 30842679 10.1038/s41591-019-0377-7

280. Bajaj JS Microbial functional change is linked with clinical outcomes after capsular fecal transplant in cirrhosis JCI Insight 2019 4 e133410 31751317 10.1172/jci.insight.133410 PMC6975263 Bajaj, J. S. et al. Microbial functional change is linked with clinical outcomes after capsular fecal transplant in cirrhosis. JCI Insight 4 , e133410 (2019). 31751317 10.1172/jci.insight.133410 PMC6975263

281. Ianiro G Faecal microbiota transplantation for the treatment of diarrhoea induced by tyrosine-kinase inhibitors in patients with metastatic renal cell carcinoma Nat. Commun. 2020 11 4333 32859933 10.1038/s41467-020-18127-y PMC7455693 Ianiro, G. et al. Faecal microbiota transplantation for the treatment of diarrhoea induced by tyrosine-kinase inhibitors in patients with metastatic renal cell carcinoma. Nat. Commun. 11 , 4333 (2020). 32859933 10.1038/s41467-020-18127-y PMC7455693

282. Hartstra AV Infusion of donor feces affects the gut-brain axis in humans with metabolic syndrome Mol. Metab. 2020 42 101076 32916306 10.1016/j.molmet.2020.101076 PMC7536740 Hartstra, A. V. et al. Infusion of donor feces affects the gut-brain axis in humans with metabolic syndrome. Mol. Metab. 42 , 101076 (2020). 32916306 10.1016/j.molmet.2020.101076 PMC7536740

283. DeFilipp Z Drug-resistant E. coli bacteremia transmitted by fecal microbiota transplant N. Engl. J. Med. 2019 381 2043 2050 31665575 10.1056/NEJMoa1910437 DeFilipp, Z. et al. Drug-resistant E. coli bacteremia transmitted by fecal microbiota transplant. N. Engl. J. Med. 381 , 2043–2050 (2019). 31665575 10.1056/NEJMoa1910437

284. Vendrik KEW Periodic screening of donor faeces with a quarantine period to prevent transmission of multidrug-resistant organisms during faecal microbiota transplantation: a retrospective cohort study Lancet Infect. Dis. 2021 21 711 721 33275940 10.1016/S1473-3099(20)30473-4 Vendrik, K. E. W. et al. Periodic screening of donor faeces with a quarantine period to prevent transmission of multidrug-resistant organisms during faecal microbiota transplantation: a retrospective cohort study. Lancet Infect. Dis. 21 , 711–721 (2021). 33275940 10.1016/S1473-3099(20)30473-4

285. Podolsky SH Metchnikoff and the microbiome Lancet 2012 380 1810 1811 23189332 10.1016/s0140-6736(12)62018-2 Podolsky, S. H. Metchnikoff and the microbiome. Lancet 380 , 1810–1811 (2012). 23189332 10.1016/s0140-6736(12)62018-2

286. Hill C Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic Nat. Rev. Gastroenterol. Hepatol. 2014 11 506 514 24912386 10.1038/nrgastro.2014.66 Hill, C. et al. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat. Rev. Gastroenterol. Hepatol. 11 , 506–514 (2014). 24912386 10.1038/nrgastro.2014.66

287. Rong Y Reactivity toward Bifidobacterium longum and Enterococcus hirae demonstrate robust CD8( + ) T cell response and better prognosis in HBV-related hepatocellular carcinoma Exp. Cell Res. 2017 358 352 359 28694023 10.1016/j.yexcr.2017.07.009 Rong, Y. et al. Reactivity toward Bifidobacterium longum and Enterococcus hirae demonstrate robust CD8( + ) T cell response and better prognosis in HBV-related hepatocellular carcinoma. Exp. Cell Res. 358 , 352–359 (2017). 28694023 10.1016/j.yexcr.2017.07.009

288. Lee B Modulation of the gut microbiota alters the tumour-suppressive efficacy of Tim-3 pathway blockade in a bacterial species- and host factor-dependent manner Microorganisms 2020 8 1395 32932843 10.3390/microorganisms8091395 PMC7564046 Lee, B. et al. Modulation of the gut microbiota alters the tumour-suppressive efficacy of Tim-3 pathway blockade in a bacterial species- and host factor-dependent manner. Microorganisms 8 , 1395 (2020). 32932843 10.3390/microorganisms8091395 PMC7564046

289. Zhuo Q Lysates of Lactobacillus acidophilus combined with CTLA-4-blocking antibodies enhance antitumor immunity in a mouse colon cancer model Sci. Rep. 2019 9 20128 31882868 10.1038/s41598-019-56661-y PMC6934597 Zhuo, Q. et al. Lysates of Lactobacillus acidophilus combined with CTLA-4-blocking antibodies enhance antitumor immunity in a mouse colon cancer model. Sci. Rep. 9 , 20128 (2019). 31882868 10.1038/s41598-019-56661-y PMC6934597

290. Lee SH Bifidobacterium bifidum strains synergize with immune checkpoint inhibitors to reduce tumour burden in mice Nat. Microbiol. 2021 6 277 288 33432149 10.1038/s41564-020-00831-6 Lee, S. H. et al. Bifidobacterium bifidum strains synergize with immune checkpoint inhibitors to reduce tumour burden in mice. Nat. Microbiol. 6 , 277–288 (2021). 33432149 10.1038/s41564-020-00831-6

291. Li Q Streptococcus thermophilus inhibits colorectal tumorigenesis through secreting beta-galactosidase Gastroenterology 2021 160 1179 1193.e14 32920015 10.1053/j.gastro.2020.09.003 Li, Q. et al. Streptococcus thermophilus inhibits colorectal tumorigenesis through secreting beta-galactosidase. Gastroenterology 160 , 1179–1193.e14 (2021). 32920015 10.1053/j.gastro.2020.09.003

292. Corb Aron RA Recognizing the benefits of pre-/probiotics in metabolic syndrome and type 2 diabetes mellitus considering the influence of Akkermansia muciniphila as a key gut bacterium Microorganisms 2021 9 618 33802777 10.3390/microorganisms9030618 PMC8002498 Corb Aron, R. A. et al. Recognizing the benefits of pre-/probiotics in metabolic syndrome and type 2 diabetes mellitus considering the influence of Akkermansia muciniphila as a key gut bacterium. Microorganisms 9 , 618 (2021). 33802777 10.3390/microorganisms9030618 PMC8002498

293. Ansaldo E Akkermansia muciniphila induces intestinal adaptive immune responses during homeostasis Science 2019 364 1179 1184 31221858 10.1126/science.aaw7479 PMC6645389 Ansaldo, E. et al. Akkermansia muciniphila induces intestinal adaptive immune responses during homeostasis. Science 364 , 1179–1184 (2019). 31221858 10.1126/science.aaw7479 PMC6645389

294. Lordan C Thapa D Ross RP Cotter PD Potential for enriching next-generation health-promoting gut bacteria through prebiotics and other dietary components Gut Microbes 2020 11 1 20 31116628 10.1080/19490976.2019.1613124 PMC6973326 Lordan, C., Thapa, D., Ross, R. P. & Cotter, P. D. Potential for enriching next-generation health-promoting gut bacteria through prebiotics and other dietary components. Gut Microbes 11 , 1–20 (2020). 31116628 10.1080/19490976.2019.1613124 PMC6973326

295. Shi L Combining IL-2-based immunotherapy with commensal probiotics produces enhanced anti-tumor immune response and tumor clearance J. Immunother. Cancer 2020 8 e000973 33028692 10.1136/jitc-2020-000973 PMC7542661 Shi, L. et al. Combining IL-2-based immunotherapy with commensal probiotics produces enhanced anti-tumor immune response and tumor clearance. J. Immunother. Cancer 8 , e000973 (2020). 33028692 10.1136/jitc-2020-000973 PMC7542661

296. Tanoue T A defined commensal consortium elicits CD8 T cells and anti-cancer immunity Nature 2019 565 600 605 30675064 10.1038/s41586-019-0878-z Tanoue, T. et al. A defined commensal consortium elicits CD8 T cells and anti-cancer immunity. Nature 565 , 600–605 (2019). 30675064 10.1038/s41586-019-0878-z

297. Montalban-Arques A Commensal Clostridiales strains mediate effective anti-cancer immune response against solid tumors Cell Host Microbe 2021 29 1573 1588.e7 34453895 10.1016/j.chom.2021.08.001 Montalban-Arques, A. et al. Commensal Clostridiales strains mediate effective anti-cancer immune response against solid tumors. Cell Host Microbe 29 , 1573–1588.e7 (2021). 34453895 10.1016/j.chom.2021.08.001

298. Roy S Trichieri G Microbiota: a key orchestrator of cancer therapy Nat. Rev. Cancer 2017 17 271 285 28303904 10.1038/nrc.2017.13 Roy, S. & Trichieri, G. Microbiota: a key orchestrator of cancer therapy. Nat. Rev. Cancer 17 , 271–285 (2017). 28303904 10.1038/nrc.2017.13

299. Das M Probiotics for chemoradiotherapy-induced oral mucositis Lancet Oncol. 2019 20 E14 30555021 10.1016/S1470-2045(18)30919-7 Das, M. Probiotics for chemoradiotherapy-induced oral mucositis. Lancet Oncol. 20 , E14 (2019). 30555021 10.1016/S1470-2045(18)30919-7

300. Jiang C A randomized, double-blind, placebo-controlled trial of probiotics to reduce the severity of oral mucositis induced by chemoradiotherapy for patients with nasopharyngeal carcinoma Cancer 2019 125 1081 1090 30521105 10.1002/cncr.31907 Jiang, C. et al. A randomized, double-blind, placebo-controlled trial of probiotics to reduce the severity of oral mucositis induced by chemoradiotherapy for patients with nasopharyngeal carcinoma. Cancer 125 , 1081–1090 (2019). 30521105 10.1002/cncr.31907

301. Consoli ML Randomized clinical trial: impact of oral administration of Saccharomyces boulardii on gene expression of intestinal cytokines in patients undergoing colon resection JPEN J. Parenter. Enter. Nutr. 2016 40 1114 1121 10.1177/0148607115584387 25917895 Consoli, M. L. et al. Randomized clinical trial: impact of oral administration of Saccharomyces boulardii on gene expression of intestinal cytokines in patients undergoing colon resection. JPEN J. Parenter. Enter. Nutr. 40 , 1114–1121 (2016). 10.1177/0148607115584387 25917895

302. Hibberd AA Intestinal microbiota is altered in patients with colon cancer and modified by probiotic intervention BMJ Open Gastroenterol. 2017 4 e000145 28944067 10.1136/bmjgast-2017-000145 PMC5609083 Hibberd, A. A. et al. Intestinal microbiota is altered in patients with colon cancer and modified by probiotic intervention. BMJ Open Gastroenterol. 4 , e000145 (2017). 28944067 10.1136/bmjgast-2017-000145 PMC5609083

303. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04988841 (Accessed 15 February 2025).

304. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03595683 (Accessed 15 February 2025).

305. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04699721 (Accessed 15 February 2025).

306. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04909034 (Accessed 15 February 2025).

307. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05094167 (Accessed 15 February 2025).

308. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT06428422 (Accessed 15 February 2025).

309. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT06768931 (Accessed 15 February 2025).

310. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05032014 (Accessed 15 February 15, 2025).

311. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05122546 (Accessed 15 February 2025).

312. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05220124 (Accessed 15 February 2025).

313. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03686202 (Accessed 15 February 2025).

314. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03775850 (Accessed 15 February 2025).

315. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03637803 (Accessed 15 February 2025).

316. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04208958 (Accessed 15 February 2025).

317. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT06508034 (Accessed 15 February 2025).

318. Lauté-Caly DL The flagellin of candidate live biotherapeutic Enterococcus gallinarum MRx0518 is a potent immunostimulant Sci. Rep. 2019 9 801 30692549 10.1038/s41598-018-36926-8 PMC6349862 Lauté-Caly, D. L. et al. The flagellin of candidate live biotherapeutic Enterococcus gallinarum MRx0518 is a potent immunostimulant. Sci. Rep. 9 , 801 (2019). 30692549 10.1038/s41598-018-36926-8 PMC6349862

319. Available online: https://www.biospace.com/4d-pharma-announces-positive-interim-results-from-the-phase-i-ii-study-of-the-combination-of-mrx0518-and-keytruda-pembrolizumab-for-the-treatment-of-renal-cell-carcinoma (Accessed 15 February 2025)

320. Tomita Y Association of probiotic Clostridium butyricum therapy with survival and response to immune checkpoint blockade in patients with lung cancer Cancer Immunol. Res. 2020 8 1236 1242 32665261 10.1158/2326-6066.CIR-20-0051 Tomita, Y. et al. Association of probiotic Clostridium butyricum therapy with survival and response to immune checkpoint blockade in patients with lung cancer. Cancer Immunol. Res. 8 , 1236–1242 (2020). 32665261 10.1158/2326-6066.CIR-20-0051

321. Tomita Y Clostridium butyricum therapy restores the decreased efficacy of immune checkpoint blockade in lung cancer patients receiving proton pump inhibitors Oncoimmunology 2022 11 2081010 35655708 10.1080/2162402X.2022.2081010 PMC9154751 Tomita, Y. et al. Clostridium butyricum therapy restores the decreased efficacy of immune checkpoint blockade in lung cancer patients receiving proton pump inhibitors. Oncoimmunology 11 , 2081010 (2022). 35655708 10.1080/2162402X.2022.2081010 PMC9154751

322. McHale D Oral delivery of a single microbial strain, EDP1503, induces anti-tumor responses via gut-mediated activation of both innate and adaptive immunity Ann. Oncol. 2020 31 S195 McHale, D. et al. Oral delivery of a single microbial strain, EDP1503, induces anti-tumor responses via gut-mediated activation of both innate and adaptive immunity. Ann. Oncol. 31 , S195 (2020).

323. Feuerstadt P SER-109, an oral microbiome therapy for recurrent Clostridioides difficile infection N. Engl. J. Med. 2022 386 220 229 35045228 10.1056/NEJMoa2106516 Feuerstadt, P. et al. SER-109, an oral microbiome therapy for recurrent Clostridioides difficile infection. N. Engl. J. Med. 386 , 220–229 (2022). 35045228 10.1056/NEJMoa2106516

324. Snigdha S Probiotics: Potential novel therapeutics for microbiota-gut-brain axis dysfunction across gender and lifespan Pharm. Ther. 2022 231 107978 10.1016/j.pharmthera.2021.107978 34492236 Snigdha, S. et al. Probiotics: Potential novel therapeutics for microbiota-gut-brain axis dysfunction across gender and lifespan. Pharm. Ther. 231 , 107978 (2022). 10.1016/j.pharmthera.2021.107978 34492236

325. Cabrita R Tertiary lymphoid structures improve immunotherapy and survival in melanoma Nature 2022 577 561 565 10.1038/s41586-019-1914-8 31942071 Cabrita, R. et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature 577 , 561–565 (2022). 10.1038/s41586-019-1914-8 31942071

326. Ruddle NH Tertiary Lymphoid Structures and Immunotherapy: Challenges and Opportunities Methods Mol. Biol. 2025 2864 299 312 39527229 10.1007/978-1-0716-4184-2_16 Ruddle, N. H. Tertiary Lymphoid Structures and Immunotherapy: Challenges and Opportunities. Methods Mol. Biol. 2864 , 299–312 (2025). 39527229 10.1007/978-1-0716-4184-2_16

327. Carmody RN Diet dominates host genotype in shaping the murine gut microbiota Cell Host Microbe 2015 17 72 84 25532804 10.1016/j.chom.2014.11.010 PMC4297240 Carmody, R. N. et al. Diet dominates host genotype in shaping the murine gut microbiota. Cell Host Microbe 17 , 72–84 (2015). 25532804 10.1016/j.chom.2014.11.010 PMC4297240

328. Le Chatelier E Richness of human gut microbiome correlates with metabolic markers Nature 2013 500 541 546 23985870 10.1038/nature12506 Le Chatelier, E. et al. Richness of human gut microbiome correlates with metabolic markers. Nature 500 , 541–546 (2013). 23985870 10.1038/nature12506

329. Wastyk HC Gut-microbiota-targeted diets modulate human immune status Cell 2021 184 4137 4153.e14 34256014 10.1016/j.cell.2021.06.019 PMC9020749 Wastyk, H. C. et al. Gut-microbiota-targeted diets modulate human immune status. Cell 184 , 4137–4153.e14 (2021). 34256014 10.1016/j.cell.2021.06.019 PMC9020749

330. Buque A Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer Nat. Commun. 2020 11 3819 32732875 10.1038/s41467-020-17644-0 PMC7393498 Buque, A. et al. Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer. Nat. Commun. 11 , 3819 (2020). 32732875 10.1038/s41467-020-17644-0 PMC7393498

331. Ferrere G Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade JCI Insight 2021 6 e145207 33320838 10.1172/jci.insight.145207 PMC7934884 Ferrere, G. et al. Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade. JCI Insight 6 , e145207 (2021). 33320838 10.1172/jci.insight.145207 PMC7934884

332. Levesque S A synergistic triad of chemotherapy, immune checkpoint inhibitors, and caloric restriction mimetics eradicates tumors in mice Oncoimmunology 2019 8 e1657375 31646107 10.1080/2162402X.2019.1657375 PMC6791453 Levesque, S. et al. A synergistic triad of chemotherapy, immune checkpoint inhibitors, and caloric restriction mimetics eradicates tumors in mice. Oncoimmunology 8 , e1657375 (2019). 31646107 10.1080/2162402X.2019.1657375 PMC6791453

333. Pietrocola F Caloric restriction mimetics enhance anticancer immunosurveillance Cancer Cell 2016 30 147 160 27411589 10.1016/j.ccell.2016.05.016 PMC5715805 Pietrocola, F. et al. Caloric restriction mimetics enhance anticancer immunosurveillance. Cancer Cell 30 , 147–160 (2016). 27411589 10.1016/j.ccell.2016.05.016 PMC5715805

334. Pomatto-Watson LCD Daily caloric restriction limits tumor growth more effectively than caloric cycling regardless of dietary composition Nat. Commun. 2021 12 6201 34707136 10.1038/s41467-021-26431-4 PMC8551193 Pomatto-Watson, L. C. D. et al. Daily caloric restriction limits tumor growth more effectively than caloric cycling regardless of dietary composition. Nat. Commun. 12 , 6201 (2021). 34707136 10.1038/s41467-021-26431-4 PMC8551193

335. Wang Y NAD+ supplement potentiates tumor-killing function by rescuing defective TUB-mediated NAMPT transcription in tumor-infiltrated T cells Cell Rep. 2021 36 109516 34380043 10.1016/j.celrep.2021.109516 Wang, Y. et al. NAD+ supplement potentiates tumor-killing function by rescuing defective TUB-mediated NAMPT transcription in tumor-infiltrated T cells. Cell Rep. 36 , 109516 (2021). 34380043 10.1016/j.celrep.2021.109516

336. Collins N The bone marrow protects and optimizes immunological memory during dietary restriction Cell 2019 178 1088 1101.e15 31442402 10.1016/j.cell.2019.07.049 PMC6818271 Collins, N. et al. The bone marrow protects and optimizes immunological memory during dietary restriction. Cell 178 , 1088–1101.e15 (2019). 31442402 10.1016/j.cell.2019.07.049 PMC6818271

337. Desai MS A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility Cell 2016 167 1339 1353.e21 27863247 10.1016/j.cell.2016.10.043 PMC5131798 Desai, M. S. et al. A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell 167 , 1339–1353.e21 (2016). 27863247 10.1016/j.cell.2016.10.043 PMC5131798

338. Tong H Dual impacts of serine/glycine-free diet in enhancing antitumor immunity and promoting evasion via PD-L1 lactylation Cell Metab. 2024 36 2493 2510.e9 39577415 10.1016/j.cmet.2024.10.019 Tong, H. et al. Dual impacts of serine/glycine-free diet in enhancing antitumor immunity and promoting evasion via PD-L1 lactylation. Cell Metab. 36 , 2493–2510.e9 (2024). 39577415 10.1016/j.cmet.2024.10.019

339. Koh A De Vadder F Kovatcheva-Datchary P Bäckhed F From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites Cell 2016 165 1332 1345 27259147 10.1016/j.cell.2016.05.041 Koh, A., De Vadder, F., Kovatcheva-Datchary, P. & Bäckhed, F. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell 165 , 1332–1345 (2016). 27259147 10.1016/j.cell.2016.05.041

340. Morrison DJ Preston T Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism Gut Microbes 2016 7 189 200 26963409 10.1080/19490976.2015.1134082 PMC4939913 Morrison, D. J. & Preston, T. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microbes 7 , 189–200 (2016). 26963409 10.1080/19490976.2015.1134082 PMC4939913

341. Coutzac C Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer Nat. Commun. 2020 11 2168 32358520 10.1038/s41467-020-16079-x PMC7195489 Coutzac, C. et al. Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer. Nat. Commun. 11 , 2168 (2020). 32358520 10.1038/s41467-020-16079-x PMC7195489

342. Sanders ME Merenstein DJ Reid G Gibson GR Rastall RA Probiotics and prebiotics in intestinal health and disease: from biology to the clinic Nat. Rev. Gastroenterol. Hepatol. 2019 16 605 616 31296969 10.1038/s41575-019-0173-3 Sanders, M. E., Merenstein, D. J., Reid, G., Gibson, G. R. & Rastall, R. A. Probiotics and prebiotics in intestinal health and disease: from biology to the clinic. Nat. Rev. Gastroenterol. Hepatol. 16 , 605–616 (2019). 31296969 10.1038/s41575-019-0173-3

343. Gibson GR Expert consensus document: the International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics Nat. Rev. Gastroenterol. Hepatol. 2017 14 491 502 28611480 10.1038/nrgastro.2017.75 Gibson, G. R. et al. Expert consensus document: the International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat. Rev. Gastroenterol. Hepatol. 14 , 491–502 (2017). 28611480 10.1038/nrgastro.2017.75

344. Becerril-Alarcon Y Inulin supplementation reduces systolic blood pressure in women with breast cancer undergoing neoadjuvant chemotherapy Cardiovasc Ther. 2019 2019 5707150 31772611 10.1155/2019/5707150 PMC6739761 Becerril-Alarcon, Y. et al. Inulin supplementation reduces systolic blood pressure in women with breast cancer undergoing neoadjuvant chemotherapy. Cardiovasc Ther. 2019 , 5707150 (2019). 31772611 10.1155/2019/5707150 PMC6739761

345. Beukema M Faas MM de Vos P The effects of different dietary fiber pectin structures on the gastrointestinal immune barrier: impact via gut microbiota and direct effects on immune cells Exp. Mol. Med. 2020 52 1364 1376 32908213 10.1038/s12276-020-0449-2 PMC8080816 Beukema, M., Faas, M. M. & de Vos, P. The effects of different dietary fiber pectin structures on the gastrointestinal immune barrier: impact via gut microbiota and direct effects on immune cells. Exp. Mol. Med. 52 , 1364–1376 (2020). 32908213 10.1038/s12276-020-0449-2 PMC8080816

346. Le Bastard Q The effects of inulin on gut microbial composition: a systematic review of evidence from human studies Eur. J. Clin. Microbiol. Infect. Dis. 2020 39 403 413 31707507 10.1007/s10096-019-03721-w Le Bastard, Q. et al. The effects of inulin on gut microbial composition: a systematic review of evidence from human studies. Eur. J. Clin. Microbiol. Infect. Dis. 39 , 403–413 (2020). 31707507 10.1007/s10096-019-03721-w

347. Panebianco C Andriulli A Pazienza V Pharmacomicrobiomics: exploiting the drug-microbiota interactions in anticancer therapies Microbiome 2018 6 92 29789015 10.1186/s40168-018-0483-7 PMC5964925 Panebianco, C., Andriulli, A. & Pazienza, V. Pharmacomicrobiomics: exploiting the drug-microbiota interactions in anticancer therapies. Microbiome 6 , 92 (2018). 29789015 10.1186/s40168-018-0483-7 PMC5964925

348. Zheng DW Prebiotics-encapsulated probiotic spores regulate gut microbiota and suppress colon cancer Adv. Mater. 2020 32 e2004529 33006175 10.1002/adma.202004529 Zheng, D. W. et al. Prebiotics-encapsulated probiotic spores regulate gut microbiota and suppress colon cancer. Adv. Mater. 32 , e2004529 (2020). 33006175 10.1002/adma.202004529

349. Han K Generation of systemic anti-tumour immunity via the in situ modulation of the gut microbiome by an orally administered inulin gel Nat. Biomed. Eng. 2021 5 1377 1388 34168321 10.1038/s41551-021-00749-2 PMC8595497 Han, K. et al. Generation of systemic anti-tumour immunity via the in situ modulation of the gut microbiome by an orally administered inulin gel. Nat. Biomed. Eng. 5 , 1377–1388 (2021). 34168321 10.1038/s41551-021-00749-2 PMC8595497

350. Zhang SL Pectin supplement significantly enhanced the anti- PD-1 efficacy in tumor- bearing mice humanized with gut microbiota from patients with colorectal cancer Theranostics 2021 11 4155 4170 33754054 10.7150/thno.54476 PMC7977465 Zhang, S. L. et al. Pectin supplement significantly enhanced the anti- PD-1 efficacy in tumor- bearing mice humanized with gut microbiota from patients with colorectal cancer. Theranostics 11 , 4155–4170 (2021). 33754054 10.7150/thno.54476 PMC7977465

351. Huang J Ginseng polysaccharides alter the gut microbiota and kynurenine/tryptophan ratio, potentiating the antitumour effect of antiprogrammed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) immunotherapy Gut 2022 71 734 745 34006584 10.1136/gutjnl-2020-321031 PMC8921579 Huang, J. et al. Ginseng polysaccharides alter the gut microbiota and kynurenine/tryptophan ratio, potentiating the antitumour effect of antiprogrammed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) immunotherapy. Gut 71 , 734–745 (2022). 34006584 10.1136/gutjnl-2020-321031 PMC8921579

352. Messaoudene M A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiota Cancer Discov. 2022 12 1070 1087 35031549 10.1158/2159-8290.CD-21-0808 PMC9394387 Messaoudene, M. et al. A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiota. Cancer Discov. 12 , 1070–1087 (2022). 35031549 10.1158/2159-8290.CD-21-0808 PMC9394387

353. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT06466434 (Accessed 15 February 2025).

354. Faria S Diet and Immune Effects Trial (DIET)- a randomized, double-blinded dietary intervention study in patients with melanoma receiving immunotherapy BMC Cancer 2024 24 1493 39633321 10.1186/s12885-024-13234-1 PMC11619607 Faria, S. et al. Diet and Immune Effects Trial (DIET)- a randomized, double-blinded dietary intervention study in patients with melanoma receiving immunotherapy. BMC Cancer 24 , 1493 (2024). 39633321 10.1186/s12885-024-13234-1 PMC11619607

355. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT06298734 (Accessed 15 February 2025).

356. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT06236360 (Accessed 15 February 2025).

357. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04866810 (Accessed 15 February 2025).

358. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03709147 (Accessed 15 February 2025).

359. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03700437 (Accessed 15 February 2025).

360. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT06671613 (Accessed 15 February 2025).

361. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05763992 (Accessed 15 February 2025).

362. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT06610097 (Accessed 15 February 2025).

363. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05083416 (Accessed 15 February 2025).

364. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT06391099 (Accessed 15 February 2025).

365. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05356182 (Accessed 15 February 2025).

366. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05832606 (Accessed 15 February 2025).

367. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT06438588 (Accessed 15 February 2025).

368. Liang K Genetically engineered Salmonella typhimurium: recent advances in cancer therapy Cancer Lett. 2019 448 168 181 30753837 10.1016/j.canlet.2019.01.037 Liang, K. et al. Genetically engineered Salmonella typhimurium: recent advances in cancer therapy. Cancer Lett. 448 , 168–181 (2019). 30753837 10.1016/j.canlet.2019.01.037

369. Chang Y Dihydromyricetin attenuates Escherichia coli lipopolysaccharide-induced ileum injury in chickens by inhibiting NLRP3 inflammasome and TLR4/NF-κB signalling pathway Vet. Res. 2020 51 72 32448367 10.1186/s13567-020-00796-8 PMC7247275 Chang, Y. et al. Dihydromyricetin attenuates Escherichia coli lipopolysaccharide-induced ileum injury in chickens by inhibiting NLRP3 inflammasome and TLR4/NF-κB signalling pathway. Vet. Res. 51 , 72 (2020). 32448367 10.1186/s13567-020-00796-8 PMC7247275

370. Taniguchi S Shimatani Y Fujimori M Tumor-Targeting therapy using gene-engineered anaerobic-nonpathogenic Bifidobacterium longum Methods Mol. Biol. 2016 1409 49 60 26846801 10.1007/978-1-4939-3515-4_5 Taniguchi, S., Shimatani, Y. & Fujimori, M. Tumor-Targeting therapy using gene-engineered anaerobic-nonpathogenic Bifidobacterium longum. Methods Mol. Biol. 1409 , 49–60 (2016). 26846801 10.1007/978-1-4939-3515-4_5

371. Gurbatri CR Arpaia N Danino T Engineering bacteria as interactive cancer therapies Science 2022 378 858 864 36423303 10.1126/science.add9667 PMC10584033 Gurbatri, C. R., Arpaia, N. & Danino, T. Engineering bacteria as interactive cancer therapies. Science 378 , 858–864 (2022). 36423303 10.1126/science.add9667 PMC10584033

372. Geiger R L-Arginine modulates T cell metabolism and enhances survival and anti-tumor activity Cell 2016 167 829 42.e13 27745970 10.1016/j.cell.2016.09.031 PMC5075284 Geiger, R. et al. L-Arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 167 , 829–42.e13 (2016). 27745970 10.1016/j.cell.2016.09.031 PMC5075284

373. Canale FP Metabolic modulation of tumours with engineered bacteria for immunotherapy Nature 2021 598 662 666 34616044 10.1038/s41586-021-04003-2 Canale, F. P. et al. Metabolic modulation of tumours with engineered bacteria for immunotherapy. Nature 598 , 662–666 (2021). 34616044 10.1038/s41586-021-04003-2

374. Leventhal DS Immunotherapy with engineered bacteria by targeting the STING pathway for anti-tumor immunity Nat. Commun. 2020 11 2739 32483165 10.1038/s41467-020-16602-0 PMC7264239 Leventhal, D. S. et al. Immunotherapy with engineered bacteria by targeting the STING pathway for anti-tumor immunity. Nat. Commun. 11 , 2739 (2020). 32483165 10.1038/s41467-020-16602-0 PMC7264239

375. Chowdhury S Programmable bacteria induce durable tumor regression and systemic antitumor immunity Nat. Med 2019 25 1057 1063 31270504 10.1038/s41591-019-0498-z PMC6688650 Chowdhury, S. et al. Programmable bacteria induce durable tumor regression and systemic antitumor immunity. Nat. Med 25 , 1057–1063 (2019). 31270504 10.1038/s41591-019-0498-z PMC6688650

376. Redenti A Probiotic neoantigen delivery vectors for precision cancer immunotherapy Nature 2024 635 453 461 39415001 10.1038/s41586-024-08033-4 PMC11560847 Redenti, A. et al. Probiotic neoantigen delivery vectors for precision cancer immunotherapy. Nature 635 , 453–461 (2024). 39415001 10.1038/s41586-024-08033-4 PMC11560847

377. Yang, S. et al. Non-pathogenic E. coli displaying decoy-resistant IL18 mutein boosts anti-tumor and CAR NK cell responses. Nat Biotechnol. (2024) Online ahead of print. 10.1038/s41587-024-02418-6 PMC12797303 39367093

378. Eng C A phase II study of axalimogene filolisbac for patients with previously treated, unresectable, persistent/recurrent loco-regional or metastatic anal cancer Oncotarget 2020 11 1334 1343 32341753 10.18632/oncotarget.27536 PMC7170499 Eng, C. et al. A phase II study of axalimogene filolisbac for patients with previously treated, unresectable, persistent/recurrent loco-regional or metastatic anal cancer. Oncotarget 11 , 1334–1343 (2020). 32341753 10.18632/oncotarget.27536 PMC7170499

379. Galicia-Carmona T ADXS11-001 LM-LLO as specific immunotherapy in cervical cancer Hum. Vaccin. Immunother. 2021 17 2617 2625 33793380 10.1080/21645515.2021.1893036 PMC8475562 Galicia-Carmona, T. et al. ADXS11-001 LM-LLO as specific immunotherapy in cervical cancer. Hum. Vaccin. Immunother. 17 , 2617–2625 (2021). 33793380 10.1080/21645515.2021.1893036 PMC8475562

380. Pennington SH Nonspecific effects of oral vaccination with live-attenuated Salmonella Typhi strain Ty21a Sci. Adv. 2019 5 eaau6849 30820452 10.1126/sciadv.aau6849 PMC6392763 Pennington, S. H. et al. Nonspecific effects of oral vaccination with live-attenuated Salmonella Typhi strain Ty21a. Sci. Adv. 5 , eaau6849 (2019). 30820452 10.1126/sciadv.aau6849 PMC6392763

381. Domingos-Pereira S Preclinical efficacy and safety of the Ty21a vaccine strain for intravesical immunotherapy of non-muscle-invasive bladder cancer Oncoimmunology 2017 6 e1265720 28197393 10.1080/2162402X.2016.1265720 PMC5283622 Domingos-Pereira, S. et al. Preclinical efficacy and safety of the Ty21a vaccine strain for intravesical immunotherapy of non-muscle-invasive bladder cancer. Oncoimmunology 6 , e1265720 (2017). 28197393 10.1080/2162402X.2016.1265720 PMC5283622

382. Drake CG Safety and preliminary immunogenicity of JNJ-64041809, a live-attenuated, double-deleted Listeria monocytogenes-based immunotherapy, in metastatic castration-resistant prostate cancer Prostate Cancer Prostatic Dis. 2022 25 219 228 34257408 10.1038/s41391-021-00402-8 PMC9184270 Drake, C. G. et al. Safety and preliminary immunogenicity of JNJ-64041809, a live-attenuated, double-deleted Listeria monocytogenes-based immunotherapy, in metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. 25 , 219–228 (2022). 34257408 10.1038/s41391-021-00402-8 PMC9184270

383. Schmitz-Winnenthal FH A phase 1 trial extension to assess immunologic efficacy and safety of prime-boost vaccination with VXM01, an oral T cell vaccine against VEGFR2, in patients with advanced pancreatic cancer Oncoimmunology 2018 7 e1303584 29632710 10.1080/2162402X.2017.1303584 PMC5889207 Schmitz-Winnenthal, F. H. et al. A phase 1 trial extension to assess immunologic efficacy and safety of prime-boost vaccination with VXM01, an oral T cell vaccine against VEGFR2, in patients with advanced pancreatic cancer. Oncoimmunology 7 , e1303584 (2018). 29632710 10.1080/2162402X.2017.1303584 PMC5889207

384. Chen YE Engineered skin bacteria induce antitumor T cell responses against melanoma Science 2023 380 203 210 37053311 10.1126/science.abp9563 PMC12356174 Chen, Y. E. et al. Engineered skin bacteria induce antitumor T cell responses against melanoma. Science 380 , 203–210 (2023). 37053311 10.1126/science.abp9563 PMC12356174

385. Preet R Gut commensal Bifidobacterium-derived extracellular vesicles modulate the therapeutic effects of anti-PD-1 in lung cancer Nat. Commun. 2025 16 3500 40221398 10.1038/s41467-025-58553-4 PMC11993705 Preet, R. et al. Gut commensal Bifidobacterium-derived extracellular vesicles modulate the therapeutic effects of anti-PD-1 in lung cancer. Nat. Commun. 16 , 3500 (2025). 40221398 10.1038/s41467-025-58553-4 PMC11993705

386. Liu XZ Bioengineered Bacterial Membrane Vesicles with Multifunctional Nanoparticles as a Versatile Platform for Cancer Immunotherapy ACS Appl. Mater. Interfaces 2023 15 3744 3759 36630299 10.1021/acsami.2c18244 Liu, X. Z. et al. Bioengineered Bacterial Membrane Vesicles with Multifunctional Nanoparticles as a Versatile Platform for Cancer Immunotherapy. ACS Appl. Mater. Interfaces 15 , 3744–3759 (2023). 36630299 10.1021/acsami.2c18244

387. Zhang J Antitumorigenic potential of Lactobacillus-derived extracellular vesicles: p53 succinylation and glycolytic reprogramming in intestinal epithelial cells via SIRT5 modulation Cell Biol. Toxicol. 2024 40 66 39110260 10.1007/s10565-024-09897-y PMC11306434 Zhang, J. et al. Antitumorigenic potential of Lactobacillus-derived extracellular vesicles: p53 succinylation and glycolytic reprogramming in intestinal epithelial cells via SIRT5 modulation. Cell Biol. Toxicol. 40 , 66 (2024). 39110260 10.1007/s10565-024-09897-y PMC11306434

388. Hsu BB Dynamic modulation of the gut microbiota and metabolome by bacteriophages in a mouse model Cell Host Microbe 2019 25 803 814.e5 31175044 10.1016/j.chom.2019.05.001 PMC6579560 Hsu, B. B. et al. Dynamic modulation of the gut microbiota and metabolome by bacteriophages in a mouse model. Cell Host Microbe 25 , 803–814.e5 (2019). 31175044 10.1016/j.chom.2019.05.001 PMC6579560

389. Selle K In vivo targeting of clostridioides difficile using phage-delivered CRISPR-Cas3 antimicrobials mBio 2020 11 e00019 e00020 32156803 10.1128/mBio.00019-20 PMC7064742 Selle, K. et al. In vivo targeting of clostridioides difficile using phage-delivered CRISPR-Cas3 antimicrobials. mBio 11 , e00019–e00020 (2020). 32156803 10.1128/mBio.00019-20 PMC7064742

390. Voorhees PJ Cruz-Teran C Edelstein J Lai SK Challenges & opportunities for phage-based in situ microbiome engineering in the gut J. Control Release 2020 326 106 119 32569705 10.1016/j.jconrel.2020.06.016 Voorhees, P. J., Cruz-Teran, C., Edelstein, J. & Lai, S. K. Challenges & opportunities for phage-based in situ microbiome engineering in the gut. J. Control Release 326 , 106–119 (2020). 32569705 10.1016/j.jconrel.2020.06.016

391. Zheng DW Phage-guided modulation of the gut microbiota of mouse models of colorectal cancer augments their responses to chemotherapy Nat. Biomed. Eng. 2019 3 717 728 31332342 10.1038/s41551-019-0423-2 Zheng, D. W. et al. Phage-guided modulation of the gut microbiota of mouse models of colorectal cancer augments their responses to chemotherapy. Nat. Biomed. Eng. 3 , 717–728 (2019). 31332342 10.1038/s41551-019-0423-2

392. Cieplak T Soffer N Sulakvelidze A Nielsen DS A bacteriophage cocktail targeting Escherichia coli reduces E. coli in simulated gut conditions, while preserving a non-targeted representative commensal normal microbiota Gut Microbes 2018 9 391 399 29517960 10.1080/19490976.2018.1447291 PMC6219645 Cieplak, T., Soffer, N., Sulakvelidze, A. & Nielsen, D. S. A bacteriophage cocktail targeting Escherichia coli reduces E. coli in simulated gut conditions, while preserving a non-targeted representative commensal normal microbiota. Gut Microbes 9 , 391–399 (2018). 29517960 10.1080/19490976.2018.1447291 PMC6219645

393. Lipska K Gumieniczek A Filip AA Anticonvulsant valproic acid and other short-chain fatty acids as novel anticancer therapeutics: Possibilities and challenges Acta Pharm. 2020 70 291 301 32074065 10.2478/acph-2020-0021 Lipska, K., Gumieniczek, A. & Filip, A. A. Anticonvulsant valproic acid and other short-chain fatty acids as novel anticancer therapeutics: Possibilities and challenges. Acta Pharm. 70 , 291–301 (2020). 32074065 10.2478/acph-2020-0021

394. Chen PB Directed remodeling of the mouse gut microbiome inhibits the development of atherosclerosis Nat. Biotechnol. 2020 38 1288 1297 32541956 10.1038/s41587-020-0549-5 PMC7641989 Chen, P. B. et al. Directed remodeling of the mouse gut microbiome inhibits the development of atherosclerosis. Nat. Biotechnol. 38 , 1288–1297 (2020). 32541956 10.1038/s41587-020-0549-5 PMC7641989

395. Reardon D EO2401 microbiome derived therapeutic vaccine + nivolumab, with/without standard continuous, or low-dose symptom directed, bevacizumab, in recurrent glioblastoma: phase 1–2 EOGBM1–18/ROSALIE study J. Immunother. Cancer 2022 10 A1 A1603 Reardon, D. et al. EO2401 microbiome derived therapeutic vaccine + nivolumab, with/without standard continuous, or low-dose symptom directed, bevacizumab, in recurrent glioblastoma: phase 1–2 EOGBM1–18/ROSALIE study. J. Immunother. Cancer 10 , A1–A1603 (2022).

396. Available online: https://www.onclive.com/view/eo2401-plus-nivolumab-and-bevacizumab-shows-activity-in-progressive-recurrent-glioblastoma (Accessed 27 February 2025)

397. Zhang S Tumor microbiome: roles in tumor initiation, progression, and therapy Mol. Biomed. 2025 6 9 39921821 10.1186/s43556-025-00248-9 PMC11807048 Zhang, S. et al. Tumor microbiome: roles in tumor initiation, progression, and therapy. Mol. Biomed. 6 , 9 (2025). 39921821 10.1186/s43556-025-00248-9 PMC11807048

398. Yousefi Y Baines KJ Maleki Vareki S Microbiome bacterial influencers of host immunity and response to immunotherapy Cell Rep. Med 2024 5 101487 38547865 10.1016/j.xcrm.2024.101487 PMC11031383 Yousefi, Y., Baines, K. J. & Maleki Vareki, S. Microbiome bacterial influencers of host immunity and response to immunotherapy. Cell Rep. Med 5 , 101487 (2024). 38547865 10.1016/j.xcrm.2024.101487 PMC11031383

399. Mrochen DM Staphylococcus aureus host tropism and its implications for murine infection models Int J. Mol. Sci. 2020 21 7061 32992784 10.3390/ijms21197061 PMC7582387 Mrochen, D. M. et al. Staphylococcus aureus host tropism and its implications for murine infection models. Int J. Mol. Sci. 21 , 7061 (2020). 32992784 10.3390/ijms21197061 PMC7582387

400. Christen U Hintermann E Animal models for autoimmune hepatitis: are current models good enough? Front Immunol. 2022 13 898615 35903109 10.3389/fimmu.2022.898615 PMC9315390 Christen, U. & Hintermann, E. Animal models for autoimmune hepatitis: are current models good enough?. Front Immunol. 13 , 898615 (2022). 35903109 10.3389/fimmu.2022.898615 PMC9315390

401. Cani PD Human gut microbiome: hopes, threats and promises Gut 2018 67 1716 1725 29934437 10.1136/gutjnl-2018-316723 PMC6109275 Cani, P. D. Human gut microbiome: hopes, threats and promises. Gut 67 , 1716–1725 (2018). 29934437 10.1136/gutjnl-2018-316723 PMC6109275

402. Allali I A comparison of sequencing platforms and bioinformatics pipelines for compositional analysis of the gut microbiome BMC Microbiol. 2017 17 194 28903732 10.1186/s12866-017-1101-8 PMC5598039 Allali, I. et al. A comparison of sequencing platforms and bioinformatics pipelines for compositional analysis of the gut microbiome. BMC Microbiol. 17 , 194 (2017). 28903732 10.1186/s12866-017-1101-8 PMC5598039

403. Lozupone CA Meta-analyses of studies of the human microbiota Genome Res. 2013 23 1704 1714 23861384 10.1101/gr.151803.112 PMC3787266 Lozupone, C. A. et al. Meta-analyses of studies of the human microbiota. Genome Res. 23 , 1704–1714 (2013). 23861384 10.1101/gr.151803.112 PMC3787266

404. Available online: https://asm.org/articles/2024/february/fecal-microbiota-transplants-past-present-future (Accessed 27 February 2025)

405. Xu F The interplay between host genetics and the gut microbiome reveals common and distinct microbiome features for complex human diseases Microbiome 2020 8 145 33032658 10.1186/s40168-020-00923-9 PMC7545574 Xu, F. et al. The interplay between host genetics and the gut microbiome reveals common and distinct microbiome features for complex human diseases. Microbiome 8 , 145 (2020). 33032658 10.1186/s40168-020-00923-9 PMC7545574

406. Qin Y Combined effects of host genetics and diet on human gut microbiota and incident disease in a single population cohort Nat. Genet. 2022 54 134 142 35115689 10.1038/s41588-021-00991-z PMC9883041 Qin, Y. et al. Combined effects of host genetics and diet on human gut microbiota and incident disease in a single population cohort. Nat. Genet. 54 , 134–142 (2022). 35115689 10.1038/s41588-021-00991-z PMC9883041

407. Ianiro G Variability of strain engraftment and predictability of microbiome composition after fecal microbiota transplantation across different diseases Nat. Med 2022 28 1913 1923 36109637 10.1038/s41591-022-01964-3 PMC9499858 Ianiro, G. et al. Variability of strain engraftment and predictability of microbiome composition after fecal microbiota transplantation across different diseases. Nat. Med 28 , 1913–1923 (2022). 36109637 10.1038/s41591-022-01964-3 PMC9499858

408. Kato S Subbiah V Kurzrock R Counterpoint: successes in the pursuit of precision medicine: biomarkers take credit J. Natl Compr. Canc Netw. 2017 15 863 866 28687573 10.6004/jnccn.2017.0127 PMC6317845 Kato, S., Subbiah, V. & Kurzrock, R. Counterpoint: successes in the pursuit of precision medicine: biomarkers take credit. J. Natl Compr. Canc Netw. 15 , 863–866 (2017). 28687573 10.6004/jnccn.2017.0127 PMC6317845

409. Bronkhorst AJ Ungerer V Holdenrieder S The emerging role of cell-free DNA as a molecular marker for cancer management Biomol. Detect Quantif. 2019 17 100087 30923679 10.1016/j.bdq.2019.100087 PMC6425120 Bronkhorst, A. J., Ungerer, V. & Holdenrieder, S. The emerging role of cell-free DNA as a molecular marker for cancer management. Biomol. Detect Quantif. 17 , 100087 (2019). 30923679 10.1016/j.bdq.2019.100087 PMC6425120

410. Rehan M Smart capsules for sensing and sampling the gut: status, challenges and prospects Gut 2023 73 186 202 37734912 10.1136/gutjnl-2023-329614 PMC10715516 Rehan, M. et al. Smart capsules for sensing and sampling the gut: status, challenges and prospects. Gut 73 , 186–202 (2023). 37734912 10.1136/gutjnl-2023-329614 PMC10715516

411. Lucchetti M Integration of multiple flexible electrodes for real-time detection of barrier formation with spatial resolution in a gut-on-chip system Microsyst. Nanoeng. 2024 10 18 38268774 10.1038/s41378-023-00640-x PMC10805851 Lucchetti, M. et al. Integration of multiple flexible electrodes for real-time detection of barrier formation with spatial resolution in a gut-on-chip system. Microsyst. Nanoeng. 10 , 18 (2024). 38268774 10.1038/s41378-023-00640-x PMC10805851

412. Jordan A Carding SR Hall LJ The early-life gut microbiome and vaccine efficacy Lancet Microbe 2022 3 e787 e794 36088916 10.1016/S2666-5247(22)00185-9 Jordan, A., Carding, S. R. & Hall, L. J. The early-life gut microbiome and vaccine efficacy. Lancet Microbe 3 , e787–e794 (2022). 36088916 10.1016/S2666-5247(22)00185-9

413. Jing N Enhancing therapeutic effects of murine cancer vaccine by reshaping gut microbiota with Lactobacillus rhamnosus GG and jujube powder Front. Immunol. 2023 14 1195075 37435064 10.3389/fimmu.2023.1195075 PMC10332846 Jing, N. et al. Enhancing therapeutic effects of murine cancer vaccine by reshaping gut microbiota with Lactobacillus rhamnosus GG and jujube powder. Front. Immunol. 14 , 1195075 (2023). 37435064 10.3389/fimmu.2023.1195075 PMC10332846

414. de Jong SE Olin A Pulendran B The impact of the microbiome on immunity to vaccination in humans Cell Host Microbe 2020 28 169 179 32791110 10.1016/j.chom.2020.06.014 PMC7422826 de Jong, S. E., Olin, A. & Pulendran, B. The impact of the microbiome on immunity to vaccination in humans. Cell Host Microbe 28 , 169–179 (2020). 32791110 10.1016/j.chom.2020.06.014 PMC7422826

415. Issrani R Reddy J Dabah THEM Prabhu N Role of oral microbiota in carcinogenesis: a short review J. Cancer Prev. 2022 27 16 21 35419305 10.15430/JCP.2022.27.1.16 PMC8984651 Issrani, R., Reddy, J., Dabah, T. H. E. M. & Prabhu, N. Role of oral microbiota in carcinogenesis: a short review. J. Cancer Prev. 27 , 16–21 (2022). 35419305 10.15430/JCP.2022.27.1.16 PMC8984651

416. Choudhry H The microbiome and its implications in cancer immunotherapy Molecules 2021 26 206 33401586 10.3390/molecules26010206 PMC7795182 Choudhry, H. The microbiome and its implications in cancer immunotherapy. Molecules 26 , 206 (2021). 33401586 10.3390/molecules26010206 PMC7795182

417. Lau HCH Zhang X Yu J Gut microbiota and immune alteration in cancer development: implication for immunotherapy eGastroenterology 2023 1 e100007 39944250 10.1136/egastro-2023-100007 PMC11770436 Lau, H. C. H., Zhang, X. & Yu, J. Gut microbiota and immune alteration in cancer development: implication for immunotherapy. eGastroenterology 1 , e100007 (2023). 39944250 10.1136/egastro-2023-100007 PMC11770436