Combination strategies of gut microbiota in cancer therapy through metabolic reprogramming and immune remodeling.

Introduction

Gut microbiota consists of bacteria, viruses, fungi, and helminths [ 1 ]. It is susceptible to environmental factors, such as diet, medicine, and lifestyle. An imbalance in gut microbiota disrupts internal environment homeostasis, leading to the rise of various diseases, including cancer. In addition to gut microbiota, the microbial communities in the TME contribute to carcinogenesis. These commensal microbiotas have been demonstrated to maintain a balance between health and carcinogenesis by remodeling immune and inflammatory responses, metabolic processes, as well as mediating cell proliferation and apoptosis [ 2 ].

Microbiota-derived metabolites support cellular energy metabolism and regulate the immune system. Compared to normal cells, tumor cells have unique metabolic characteristics. Metabolic transitions are also carried out by other highly proliferating cells, such as stromal and immune cells [ 3 ]. Tumor cells restrict the metabolism of tumor-infiltrating immune cells through nutrient deprivation, creating an immunosuppressive microenvironment [ 4 ]. Microbiota-derived metabolites are taken up into the bloodstream and then spread all over the body, such as short-chain fatty acids (SCFAs) [ 5 ], bile acids [ 6 ], amino acids [ 7 ], and reactive oxygen species (ROS) [ 8 ]. These metabolites participate in the cross-talk between tumor cells and immune cells and the regulation of physiology and immune.

With age, the prevalence of cancer increases sharply, peaking at around 85 or 90 years old [ 9 ]. The high incidence of cancer in the elderly is associated with gut microbiota dysbiosis. This alteration promotes the development of chronic inflammation, epigenetic modifications, and mitochondrial structural and functional abnormalities [ 10 ], leading to an immunosenescence environment. Immunosenescence, particularly excessive T cell senescence, ultimately results in a deterioration in immune system function and induces potential tumorigenic process [ 11 ].

Immunotherapy, including oncolytic viruses (OVs), chimeric antigen receptor T-cell therapy (CAR-T), and immune checkpoint inhibitors (ICIs), has revolutionized the treatment of cancer. Immunotherapy, as well as traditional radiation and chemotherapy, have yet to reach their full therapeutic potential. The effectiveness of these therapies varies from person to person. Even worse, there are severe adverse effects, and tumor cells exhibit innate or acquired resistance during therapy. Increasing evidence suggests that gut microbiota modulates the efficacy of cancer treatment, particularly immunotherapy. Sivan et al. were the first to propose that oral administration of probiotics significantly enhance the efficacy of ICIs [ 12 ]. Additional experiments by other scientists further show that gut microbiota may influence immunotherapy by stimulating immune cells and increasing the immunogenicity of tumor cells. Bacteroides fragilis , for instance, increases interleukin (IL)−12-dependent T helper 1 (Th1) immune responses by activating dendritic cells (DCs) in lamina propria, reversing anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) non-responsiveness [ 13 ]. Engineered bacteria that express the tail length tape measure protein (TMP) activate the immune system through molecular mimicry, improving clinical outcomes of anti-programmed death 1 (PD-1) immunotherapy [ 14 ]. Studies conducted both in vitro and in vivo have also demonstrated the potential of modifying gut microbiota to enhance the effects of radiation treatment, chemotherapy, and traditional Chinese medicine (TCM) [ 15 – 17 ].

Polymeric microbiome technologies, including microbial metagenomics, metatranscriptomics, metaproteomics, and metabolomics, now enables researchers to make breakthroughs in comprehending the interactions among gut microbiota, host physiology, immunity, and oncology. Studies have identified specific gut microbial composition is closely related to the toxicity and responsiveness of immunotherapy and radiochemotherapy [ 18 – 20 ].

Altering the composition and the living environment of gut microbiota has been demonstrated to optimize tumor treatment. Microbiota-based therapies, including untargeted therapies (e.g., dietary intervention, probiotics and prebiotics, fecal microbiota transplantation [FMT]) and targeted techniques (e.g., phage therapy, engineered microbes, nanomedicine-based drug delivery, outer membrane vesicles [OMVs]), hold promise in future treatment. These microbiota-based strategies exhibit potent therapeutic potential by modulating the composition of gut microbiota, activating the immune system, influencing tumor biological behavior, and strengthening the intestinal barrier. For instance, results from a phase II clinical trial have indicated that FMT restored microbiota diversity in patients with PD-1-refractory melanoma and dramatically improved the safety and responsiveness to ICIs [ 21 ]. Some microorganisms have been engineered as immune activators or drug transporters. Yue et al. designed an oral tumor vaccine based on Escherichia coli that released effective OMVs. By overcoming the intestinal barrier and maximizing the intestinal immune response, the tumor vaccination model efficiently eradicated tumor cells [ 22 ].

In this review, we discuss the latest insights into the role of gut microbiota in tumor metabolic reprogramming, the TME and the aging microenvironment remodeling. We also discuss whether gut microbiota can act as an effective adjunct to tumor treatment. Finally, we emphasize the feasibility of both targeted and non-targeted microbiota strategies in cancer therapy.

Gut microbiota and cancer metabolic reprogramming

Tumor cells undergo metabolic reprogramming. They produce metabolic toxins, cause nutrient deprivation, and interfere with metabolic signals, impairing the function of immune cells. It’s the process which promotes tumor immune escape. Gut microbiota metabolites are capable of participating in the cancer cells metabolic reprogramming and immune remodeling (Fig. 1 ). This section will focus on how the metabolic interaction network mediated by gut microbiota builds a communication bridge between tumor cells and immune cells. Fig. 1 Gut microbiota modulation in cancer metabolic reprogramming. A Glycometabolism. Lactic acid increases the expression of PD-L1 of neutrophils, suppressing T cell activities; Butyrate acts as HDACi, promoting apoptosis in tumor cells. Butyrate also facilitates the dephosphorylation and tetramerization of dimeric PKM2, a process that inhibits the Warburg metabolism of tumor cells. B Lipid metabolism. SCFAs increase IgA antibody in the intestinal mucosa and inhibit the PI3 K-Akt signaling pathway. They also bind to the FFAR2 receptor, increasing E-cadherin expressions. But the excessive accumulation of SCFAs promotes the transformation of immunosuppressive cells; DCA promotes the translocation of RelA (p65) to the nucleus,activating the NF-κB signaling pathway. UDCA restricts the activity of DCA, reducing the production of inflammatory factors. DCA also works with lipoteichoic acid, inhibiting COX-2 production. C Protein metabolism. Tumor cells and immune cells compete for amino acids.The expression of the glutamine receptor increases in cancer cells, helping them to absorb more amino acids. Gut microbiota produces hydrolase enzymes, which disrupts the epithelial barrier. D ROS production. ROS cause genetic mutations, DNA breaks, and chromosomal instability. MCT1, monocarboxylate transporter1; HDACi,histone deacetylase inhibitor; PKM2, pyruvate kinase isozyme type M2; SCFAs, short-chain fatty acids; FFAR2, free fatty acid receptor 2; TAM, tumor-associated macrophage; DCA, deoxycholic acid; UDCA, ursodeoxycholic acid;COX-2, Cyclooxygenase-2; HSC, hepatic stellate cell; E. faecalis, Enterococcus faecalis; B. fragilis, Bacteroides fragilis ; GelE, gelatinase; BFT, fragilysin; ROS, reactive oxygen species

Glycometabolism

Warburg metabolism represents a distinct mode of cancer energy metabolism. Its core characteristic lies in the fact that, even with sufficient oxygen, cancerous tissues are more likely to follow glycolysis pathway rather than OXPHOS pathway. This abnormal metabolic pattern is characterized by a significant production of lactate, a lower yield of adenosine triphosphate (ATP), the shunting of glycolytic intermediates, and the remodeling of microenvironment [ 23 ]. Accumulation of lactate stimulates Propionibacterium freudenreichii to produce acetic acid which could further modulate the metabolic reprogramming of cancer cells [ 24 ]. Bacteria with the ldh, mgsA, and lldD genes have been correlated with the facilitation of lactate production[ 25 ]. In neutrophils, lactate activates the MCT1/NF-kB/COX-2 pathway, which raises programmed death ligand 1 (PD-L1) expression. And T cell cytotoxicity is decreased because of the increased PD-L1 + neutrophils [ 26 ]. The acidic TME impairs immune cells, promotes tumor-associated angiogenesis and enhances cancer invasion and metastasis [ 27 ].

Butyrate is a kind of fermentation product of polysaccharides, mainly produced by the Firmicutes phylum , but also Actinobacteria , Bacteroidetes , Fusobacteria and others [ 28 ]. It is the preferred source of normal colon cells. When colonocytes become cancerous, the main energy source changes from butyrate to glucose [ 29 ]. As a result, the pathway to tricarboxylic acid cycle (TCA) of butyrate is blocked, resulting in its accumulation in the cancerous cells and nucleus. There, it acts as an histone deacetylase inhibitor (HDACi), interfering with the cell cycle and promoting apoptosis of cancerous colonocytes [ 30 ].

Pyruvate kinase M2 (PKM2), a key enzyme in the glycolytic pathway, is an important regulatory factor in Warburg metabolism. The dimeric PKM2 promotes the anabolic pathways that store phosphate metabolites as biosynthetic precursors for tumor progression [ 31 ]. Butyrate contributes to dephosphorylation and tetramerization of PKM2. The alteration suppresses the Warburg effect and redirects the anabolic metabolism towards energy metabolism, inhibiting tumorigenesis [ 32 ]. Dimer PKM2 is also capable of translocating to the nucleus, where it binds to hypoxia-inducible factor 1α (Hif-1α). This process regulates the expression of PD-L1 in immune and tumor cells, creating a immunosuppressive environment [ 33 ]. Additionally, nuclear PKM2 stimulates the phosphorylation of STAT3, enhancing the expression of IL-17 in CD4 + T cells [ 34 ].

Butyrate exerts its beneficial effects through many other mechanisms. When the internal environment is relatively balanced, it suppresses the pH of feces in the gut to inhibit DNA damage and the proliferation of pathogens as an acid [ 35 ]. While cancerous cells are detected, butyrate regulates certain signaling pathways to maintain intestinal homeostasis. For example, it weakens Wnt/βcatenin signaling to control cell proliferation and epithelial differentiation [ 36 ]. It also promotes toll-like receptor 4 (TLR4) mediated NF-κB signaling which enhances innate immunity [ 37 ].

Lipid metabolism

SCFAs and bile acids are two primary categories of microbiota lipid metabolites. We will discuss the way they impact cancer progression, mainly focusing on how they influence the immune system and tumorigenesis pathways.

SCFAs

SCFAs are the anaerobic microbiota-derived metabolites. They have a dual influence on the occurrence and development of tumors. On the one hand, SCFAs have a reputation for maintaining immunity. They function as effective signaling molecules which stimulate the production of protective lgA in mucosal tissues and reinforce the integrity of the epithelial barrier [ 5 ]. SCFAs produced by the fermentation of starch by the fungus Schizosaccharomyces octosporus have even been shown to enhance the therapeutic efficacy of ICIs [ 38 ]. SCFAs also exert an inhibitory effect on the biological behavior of cancer cells. Taking colorectal cancer (CRC) for an example, SCFAs facilitate apoptosis by inhibiting the phosphorylation of Bad that activates caspase-3, thereby blocking the PI3 K-Akt signaling pathway [ 36 ]. In breast cancer cells, SCFAs also inhibit Hippo/YAP signaling pathway by binding to FFAR2, leading to an increase in E-cadherin expression, effectively preventing tumor invasion and metastasis [ 39 ].

On the other hand, with the advancing of research, SCFAs have been shown to exhibit negative effects in cancer prevention and treatment. Systemic SCFAs have been confirmed to diminish the efficacy of anti-CTLA-4 therapy by reducing the expression of ICOS molecules on CD4⁺ T cells and the expression of CD80/CD86 molecules on DCs [ 40 ]. And the abnormal aggregation of lipid metabolites in tumor-infiltrating myeloid cells might induce the transformation of the immune cells into anti-inflammatory and immunosuppressive phenotypes [ 4 ]. The contradictory effects of SCFAs highlights the importance of a more sophisticated interpretation of SCFAs’ role in carcinogenesis and tumor progression.

Bile Acids

Bile Acids are the endogenous chemicals produced from cholesterol in the liver. They are subsequently carried into the intestine and converted by gut bacteria into secondary bile acids. By attaching to nuclear receptors, bile acids could reprogram the transcriptional signaling of inflammation-related genes [ 41 ]. The secondary bile acid deoxycholic acid (DCA) induces the nuclear translocation of RelA (p65), which activates the NF-κB signaling pathway. The process potentially intensifies inflammatory reactions. Ursodeoxycholic acid (UDCA), on the other hand, has an anti-inflammatory impact by inhibiting the activity of DCA [ 36 ]. Furthermore, DCA promotes the conversation of hepatic stellate cells (HSCs) into senescence-associated secretory phenotype (SASP), which secretes a considerable number of inflammatory and pro-tumorigenic factors, increasing the risk of cancer [ 6 ]. When combined with DCA, lipoteichoic acid increases the expression of SASPs and COX2, resulting in an immunosuppressive microenvironment [ 42 ].

Protein metabolism

More and more research findings elucidate the influence of gut microbiota on immune remodeling and intestinal mucosal integrity via protein metabolism (Fig. 1 ). The multifaceted interaction between protein metabolism and oncogenesis will be reviewed here, with a specific emphasis on amino acid metabolism and enzyme production.

Amino acid metabolism

The homeostasis of amino acid metabolism in the circulatory system and the gastrointestinal tract is maintained largely by gut microbiota. Clostridium metabolizes branched-chain amino acids, arginine, and proline [ 43 ]. The Peptostreptococcus genus has been observed to metabolize glutamate and tryptophan [ 7 ]. Gut microbiota is also capable of synthesizing amino acids. At specific concentration, Streptococcus bovis has been identified to contribute to the de novo synthesis of amino acids [ 7 ].

Research shows that amino acid metabolism remodels tumor immunity. Malignant cells have enhanced amino acid absorption, which results in a depletion of amino acids in the TME [ 44 ]. T cell activation is inhibited by this decrease because it affects how well T cells use the amino acids [ 45 ]. Polyamines are a type of aliphatic amines synthesized from amino acid metabolism in both microbiota and host tissues. Zheng et al. clarified that polyamine metabolism is linked to the microbial communities that are abundant in the feces of patients who are responding to anti-PD-1 therapy [ 46 ]. However, it is still unknown how exactly gut microbiota affects immunotherapy through polyamine metabolism.

Amino acid metabolism is also closely linked to protecting the intestinal mucosal barrier. Lactobacillus , Anaerostipes and Bifidobacterium , along with others, catabolize tryptophan into indole derivatives. The bioactive compounds enhance the intestinal barrier function in germ-free mice by stimulating the Pregnane X Receptor [ 47 ]. A tryptophan-deficient diet administered to aged mice have been proved to result in an reduction in microbiota diversity and an increase in the levels of circulating inflammatory cytokines [ 48 ].

A correlation has been identified between amino acid metabolism and tumor physiology. There is an increased expression of the glutamine transporters in colorectal cancerous tissues [ 49 ]. Glutamine supplies α-ketoglutaric acid for TCA cycle and protects the integrity of the mitochondrial membrane, thereby inhibiting oxidative stress and fostering the growth of these malignant cells [ 50 ].

Enzyme production

Gut microbiota has the capacity to produce enzymes that damage the intestinal mucosa, trigger cancer-promoting signal cascades and impact gene stability. Enterococcus faecalis produces a metalloprotease known as GelE, which impairs the integrity of the epithelial barrier and causes chronic inflammation [ 51 ]. BFT is a zinc-dependent metalloprotease toxin produced by Bacteroides fragilis. It breaks down E-cadherin because of its proteolytic activity. The absence of E-cadherin not only enhances colon permeability but also triggers the Wnt/β-catenin signaling pathway, which in turn promotes the expression of the proto-oncogene MYC and colonic cell proliferation [ 52 ].

ROS production

Bacteria promote the accumulation of ROS either by directly producing ROS themself or by facilitating ROS production in host cells. It has been established that Lactococci , Enterococci and Helicobacter pylori , directly generate ROS in the form of superoxide [ 8 ]. While anaerobic bacteria bind to TLR2 or TLR4 on intestinal epithelial cells, enhancing ROS levels indirectly [ 35 ].

The impact of ROS on tumors can be either beneficial or detrimental, depending on the time and concentration of ROS involved. On the negative side, ROS cause DNA damage and genomic instability. E. faecalis are capable of producing hydroxyl radical, which causes genetic mutations, DNA breaks, and chromosomal instability, increasing the risk of CRC [ 35 ]. On the positive side, high ROS concentration kill tumor cells through ferroptosis, necroptosis, and apoptosis [ 53 ]. Tumors try to protect themselves from ROS damage by producing antioxidants. TIGAR levels were upregulated in precancerous lesions, where they reduce ROS levels by increasing NADPH and activating the pentose phosphate pathway [ 54 ]. In conclusion, the accumulation of ROS has a double-edged sword effect on tumors. In the field of cancer treatment, more targeted therapeutic approaches can be developed based on the relationships among ROS, microbiota, and oncology. At different stages of tumors, the development and occurrence of tumors can be prevented by dynamically intervening in the levels of ROS. In the pre-cancerous stage, the production of ROS can be inhibited. While in the advanced stage of tumorigenesis, the concentration of ROS can be increased to promote the death of tumor cells.

Other cancer-related metabolism

Hydrogen sulfide (H 2 S), the toxic gas produced by gut microbiota from sulfur-containing compounds, exhibits a dual role in the intestinal mucosa. Historically, it has been recognized that H 2 S disrupts the energy metabolism of colonic epithelial cells by inhibiting mitochondrial electron transport. However, recent studies have revealed that low concentration of H 2 S is actually helpful for mitochondrial function [ 55 ]. The double-sword characteristics of H 2 S emphasizes the necessity for a comprehensive approach to elucidate its function in carcinogenesis and progression.

Additional microbial metabolites like succinate and trimethylamine n-oxide (TMAO) affect glucose metabolism [ 56 , 57 ]. Once gut microbiota is in a condition of dysfunction and disturbance, the levels of these metabolites change, increasing the risk of carcinogenesis.

Gut microbiota and TME remodeling

Gut microbiota dysbiosis induces TME formation, shaping an immunosuppressive microenvironment. In the TME, different types of cells engage in crosstalk through complex metabolic interference mechanisms. The crosstalk promotes the immune escape of tumor cells and drives the progression of tumor development. In this section, we will focus on exploring how gut microbiota influences the TME through aging-associated and metabolic-associated TME remodeling.

Aging-associated TME remodeling

Generally, most cancers are more likely to occur in older people [ 9 ]. Both cancer and aging involve the accumulation of cell damage and share features such as gut microbiota dysbiosis, epigenetic alterations, chronic inflammation, and mitochondrial dysfunction. The diversity of bacterial communities in adults decreases with age [ 58 ], with shifts in bacterial composition. It also varies in tumors [ 59 ], suggesting its role in reshaping TME.

Epigenetic modifications are crucial in cancer development and aging. It is widely acknowledged that epigenetic abnormalities can lead to tumorigenesis. And gut microbiota and their metabolites have to been demonstrated to regulate histone modifications, DNA methylation, and non-coding RNA [ 60 ]. Gut microbiota dysbiosis with age, may induce epigenetic alterations that promote tumorigenesis. Chronic inflammation is a distinct characteristic of cellular aging. With age, cells change into SASPs [ 61 ]. These cells are capable of increasing the expression of pro-inflammatory cytokines, enzymes, chemokines, and growth factors. Over time, age-related accumulation of SASP factors creates a chronic inflammatory microenvironment [ 62 ]. With age, the mutation rate of mitochondrial DNA (mtDNA) increases [ 63 ]. MtDNA mutations and copy numbers change dynamically, altering metabolic state of the cells in the TME. For example, reduction of mtDNA copy number in human mammary epithelial cells (hMECs) initiates EMT-like reprogramming, leading to a fibroblastic morphology and an invasive phenotype [ 64 ]. And it has been shown that chronic infections with H.pylori and E.faecalis can induce mtDNA mutations that impair cellular respiration [ 8 ].

Comprehensive studies of the relationship between cancer and aging have identified the regulatory role of gut microbiota in several similar pathophysiological processes. As individuals age, gut microbiota dysbiosis may lead to epigenetic changes, chronic inflammation and damage to mitochondrion. Immunosenescence is an age-related immune dysfunction [ 65 ]. It is accelerated by the four traits that the TME and the aging microenvironment have in common. Madison et al. have identified a correlation between lower gut microbial diversity and higher T cell senescence and DNA methylation [ 66 ]. Chronic stimulation by commensal bacteria induces senescence in lymphoid germinal center (GC) B cells, leading to a reduction in IgA and disruption of mucosal immunity. The composition of gut microbiota is further altered by a loss in IgA, establishing a vicious cycle that harms intestinal homeostasis [ 65 ]. To disrupt the pathogenic network, treatment targeting the four hallmarks should be considered. We could utilize microbiota-directed therapies to restore youthful microbial profiles, which may further exert a positive effect on modifying the epigenome, inhibiting chronic inflammation, and reshaping the stability of mitochondrial function. Furthermore, normalizing the epigenetic landscape can be achieved by the drugs that target epigenetic regulators such as SCFAs. By intervening in the shared nodes of the cancer-aging-microbiota axis, these interventions hold promise not only for cancer prevention but also for extending the health span in aging populations.

Metabolic-associated TME remodeling

The TME is a complex ecosystem comprising neoplastic cells, immune cells, endothelial cells, stromal cells, extracellular matrix, and a variety of signaling molecules [ 67 ]. The main ones are Firmicutes and Proteobacteria , and they have an impact on the TME [ 5 ]. For example, Fusobacterium. nucleatum binds to the immune checkpoint receptor tyrosine-based inhibitory motif (TIGIT) on cells, which limits the cytotoxic activity of natural killer (NK) cells [ 68 ]. Different cells within the TME engage in metabolic crosstalk. The tumor metabolic by-products may act as signaling molecules to interfere with the normal metabolic patterns of cells in the TME. The shift in the metabolic patterns of normal cells further creates a favorable environment for tumor metabolism, forming a vicious cycle. For instance, cancer cells release ROS that promotes the metabolic transition of cancer-associated fibroblasts (CAFs) to aerobic glycolysis. The process delivers the energy-rich substances for tumor growth [ 44 ]. It is worth noting that tumors display considerable metabolic heterogeneity. Tumor cells closer to blood vessels have better access to oxygen and nutrients. They obtain energy more through OXPHOS compared to tumor cells farther away from blood vessels [ 69 ]. When tumors metastasize, they may have new metabolic phenotype due to the different nutrient supply.

Strategies targeting the TME may represent novel approaches for cancer treatment. For instance, developing targeted drugs to specifically block the binding between F. nucleatum and TIGIT might be an effective means of regulating bacterial-immune interactions and activating the immune response. We can also block the metabolic support system in the TME, such as accelerating the clearance of tumor metabolic toxins and inhibiting the supply of tumor metabolic substrates. In the light of tumor metabolic heterogeneity, it is necessary to develop inhibitors targeting the OXPHOS or glycolysis pathways based on the distinct metabolic patterns of tumors. In conclusion, the TME provides a variety of potential targets for future cancer prevention and treatment.

Combination strategies of Gut microbiota in cancer therapy

Gut microbiota and clinical efficacy of anticancer combination therapy

Emerging evidence highlights the role of gut microbiota and their metabolites in driving TME remodeling. The regulatory effects on the metabolism of immune and tumor cells can not be underestimated. Elucidating how these microbiota-mediated mechanisms modulate therapeutic response to cancer therapies will provide crucial insights for optimizing combinatorial treatment strategies. In detail, gut microbiota impacts the efficacy of antitumor therapies by remodeling immune responses and drug metabolism. In the subsequent sections, we will explore in detail the roles of gut microbiota in various oncological treatment strategies.

Immunotherapy

Based on the microbiota-cancer metabolism-immune axis revealed by the above research, it has been clearly established that gut microbiota can activate the anti-tumor immune response by disturbing tumor metabolic reprogramming in the TME. It is of great scientific value to further analyze the mechanism of how the immune regulation mediated by gut microbiota influences the immunotherapy. Notably, it activates the immune system through stimulating immune cells, modulating cytokine secretion, regulating immune checkpoint expression, and increasing tumor cell immunogenicity, which significantly improves the efficacy of immunotherapies (Fig. 2 ). Fig. 2 An overview of mechanisms of how gut microbiota increases the efficiency of immunotherapies. A ICIs. LGG activates cGAS/STING pathway in DCs, promoting CD8 + T cell and NK cell activation; Inosine binds to A2 AR on T cells, promoting the activation of TH1 cells; C. cateniformis reduces the expression of PD-L2 in DCs; B. breve and E. hirae share antigenic similarities with tumors, enhancing the cross-reactive response of CD8 + T cells. B CAR-T therapy. SCFAs activate mTOR and inhibit the activity of deacetylases. C CpG-ODN immunotherapy: CpG-ODN activates the TLR9 receptor on myeloid cells, triggering a Th1-type immune response. Gut microbiota binds to the TLR4, increasing cytokine production and the efficacy of CpG-ODN immunotherapy. D OVs: OVs target tumor cells, promoting ICD. Bifidobacterium have similar antigen with tumor cells, triggering the cross-reactive effects. LGG, Lactobacillus rhamnosus GG; A2 AR, adenosine A 2 A receptor; C. cateniformis, Coprobacillus cateniformis; RGMb, repulsive guidance molecule b; B.breve, Bifidobacterium breve ; E. hirae, Enterococcus hirae ; mTOR, mammalian target of rapamycin; TLR, toll-like receptor; OV,oncolytic virus; ICD, immunogenic cell death; TAAs, tumor-associated antigens; PAMPs, pathogen-associated molecular patterns; DAMPs, damage-associated molecular patterns

ICIs

ICIs open a revolutionary new chapter in oncological treatment. Gut microbiota modulates the efficacy of ICIs by directly activating immune cells. In vitro and in vivo experiments have shown that the combination of anti-PD-1 with Lactobacillus rhamnosus GG (LGG) improved the efficacy of immunotherapy. LGG stimulates the cGAS/STING pathway in DCs, promotes type I Interferon (IFN I) production, and enhances CD8 + T cell and NK cell activity, exhibiting strong suppression against CD11c − MHCII + tumor cells [ 70 ]. Mager et al. found that the inosine from Bifidobacterium pseudolongum activates the adenosine A 2 A receptor specifically on T cells, promoting the activation of TH1 cells as well [ 71 ]. Furthermore, Coprobacillus cateniformis reduces PD-L2 expression in DCs and inhibits the PD-L2 receptor RGMb on T cells, which promotes the anti-tumor reaction. It has been identified as an effective way to overcome anti-PD-1 or anti-PD-L1 immunotherapy resistance [ 72 ].

Gut microbiota enhances the immune response by increasing the immunogenicity of tumor cells. Certain commensal microbes share similar antigens with tumors. When T cells recognize microbial antigens, they cross-react with tumor-associated antigens. The cross-reactive T cells causes a stronger immune response. For instance, the SVYRYYGL (SVY) epitope of Bifidobacterium breve is similar to the tumor-expressed neoepitope antigen SIYRYYGL (SIY). SVY-specific T cells significantly inhibit the growth of B16-SIY tumors [ 73 ]. Vsamizizou et al. demonstrated that when specific T cells from the Bacteroides thetaiotaomicron or Bacteroides fragilis were introduced into a mouse model, the mice's unresponsiveness to CTLA-4 treatment was overcome [ 13 ]. Fluckiger’s team further validated the hypothesis that microbial-tumor cross-antigen reactions may enhance the efficacy of ICIs. They found that TMP of E. hirae was highly similar to the tumor PSMB4 antigen. Both antigens activate large numbers of CD8 + T cells, improving the therapeutic efficacy of ICIs [ 14 ].

Anti-PD-1/PD-L1 and anti-CTLA-4 primarily target secondary immune responses. CD47 is an innate immune checkpoint that is over-expressed on nearly all tumor cells [ 74 ]. It interacts with signal regulatory protein-alpha (SIRPα) on the surface of macrophages, preventing the phagocytosis of tumor cells [ 75 ]. Anti-CD47-SIRPα has emerged as a therapeutic strategy for the next generation of ICIs. Shi’s team has showed that Bifidobacterium colonized in the tumor and enhanced the efficacy of anti-CD47 immunotherapy by activating the STING signaling pathway in DC cells [ 76 ]. The research opens a new avenue for combination of microbiota and immunotherapy in cancer treatment.

CAR-T

CAR-T cell therapy has achieved unprecedented success in treating recurrent/refractory (R/R) hematological malignancies [ 77 ]. However, at the time of writing this article, research findings on how gut microbiota affects the efficacy of CAR-T cell therapy are relatively limited. This review aims to explore the potential links between gut microbiota and CAR-T therapy and the mechanisms, which may provide a new perspective for the field.

In recent years, several clinical trials have revealed that specific gut microbial taxa, such as Ruminococcus, Faecalibacterium, Bacteroides, Sutterella , and Akkermansia , predicts better outcomes for CAR-T cell therapy [ 78 – 80 ]. High-risk antibiotics with broad-spectrum and anti-pseudomonal capabilities before CAR-T cell infusion, has been associated with a decrease in efficacy [ 78 ]. The reduced efficacy of adoptive cell therapy (ACT), may be explained by the depletion of certain bacterial metabolic products in the host, such as short SCFAs, which is caused by these anaerobic bacteria targeting antibiotics. Luu et al. showed that SCFAs enhance the potency of CAR-T cells by inhibiting the function of HDAC and increasing mTOR activity [ 81 ]. However, in mice treated with CD19 CAR-T cell therapy and vancomycin, an antibiotic targeting gram-positive bacteria, systemic CD8α + DCs and IL-12 increase, leading to the improved therapeutic outcomes [ 82 ]. Therefore, the appropriate selection of antibiotics in combination with ACT immunotherapy may bring new treatment strategies and better clinical results for cancer treatment.

OVs

OVs exert their antitumor effects either directly by targeting and lysing tumor cells or indirectly by activating the immune system (Fig. 2 ) [ 83 ]. Human enteroviruses stand out as the most prevalent and effective reservoir among the several sources. Notably, some oncolytic enteroviruses have been shown to specifically target tumor cells, including Echovirus, Coxsackievirus B3 (CV-B3), and Coxsackievirus A21 (CV-A21) [ 84 ].

OVs turn “cold” tumors into “hot” tumors. They induce cell death by apoptosis, necrosis, and autophagy, and others, when they infect malignant cells. This process is known as immunogenic cell death (ICD). It releases tumor-associated antigens (TAAs), pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs), activating both non-specific and specific immune responses [ 85 ]. Because of the mechanism, OVs can be used as effective primers for immunotherapies like ICIs and CAR-T. Kim et al. found that CF33 infection increases PD-L1 levels and TIL infiltration. When CF33 derivatives were combined with anti-PD-L1 therapy, tumor growth in CRC mouse model was controlled, and a better prognosis was achieved [ 86 ].

Gut microbiota contributes to the regulation of the antitumor effects of OVs through the activation of immune responses. For example, melanoma and Bifidobacterium -derived epitopes share cross-reactive antigens, which activates T cells and thereby enhances the efficacy of OVs [ 87 ]. Xia et al. found that probiotics or FMT reversed the low responsiveness of oncolytic virus vaccines to advanced CRC. This enhancement is potentially mediated by the activation of CD8 + T cells and a decrease in the percentage of Treg cells [ 88 ].

CpG-oligonucleotide immunotherapy

CpG-oligonucleotide (CpG-ODN) immunotherapy is another approach to treating cancer by activating the host immune system. CpG-ODN acts as an agonist for TLR9 on myeloid cells, which triggers a powerful Th1-type immune response [ 89 ]. Tumor-associated myeloid cells'reactivity to CpG-ODN can be improved when gut microbiota activates TLR4 on these cells. In germ-free or antibiotic-treated CRC or melanoma mouse models, there is a reduction in the production of IL-12 and tumor necrosis factor (TNF) after the CpG-ODN immunotherapy, leading to the poor response to the treatment [ 90 ].

Overall, gut microbiota influences the responsiveness of various immunotherapies by activating the immune system and turning “cold” tumors into “hot” tumors. Precisely targeting gut microbiota may help to improve the efficacy of immunotherapies and provide more personalized treatment options for patients.

TCM

TCM has been utilized as a successful complementary treatment for cancer, particularly in China. Its specific anticancer mechanisms remain unclear. But it is very promising that TCM works with gut microbiota to directly modulate cell proliferation and immune responses, or indirectly affect the efficacy of other cancer therapies to enhance anti-tumor effects.

TCM is mainly administered orally. Its digestion and absorption in the gastrointestinal tract inevitably interact with gut microbiota. Through a sequence of biochemical events, gut microbiota alters the TCM components, which may have an impact on their therapeutic effectiveness. For instance, baicalin can be converted into baicalein. The former has limited anti-proliferative effects on cancer cells, whereas the latter arrests the cell cycle at the S-phase and has a strong pro-apoptotic effect [ 91 ]. Moreover, Ferulic acid can be transformed into 4-vinylguaiacol, which demonstrates inhibitory effects on the G1-phase of the cell cycle and induces apoptosis as well [ 17 ].

TCM also modulates the composition of gut microbiota. Certain TCM compound formulas or single herbes, including but not limited to Pien Tze Huang [ 92 ], Tetrastigma hemsleyanum Diels et Gilg [ 93 ], and Sini Decoction [ 94 ], have strong anti-tumor effects by increasing the abundance of probiotics and reducing the pathogenic bacteria.

The synergistic effect of TCM and microbiota to regulate other cancer treatments cannot be overlooked. Poria cocos polysaccharides (PCPs) enhance the efficacy of 5-FU by reshaping gut microbiota, reducing the toxicity, regulating the production of inflammatory factors, and improving the intestinal barrier [ 95 ]. The process of TCM reshaping gut microbiota inevitably affects the production of metabolic products. When combined with anti-PD-1 immunotherapy, Ginseng polysaccharides (GPs) reduce the ratio of Kyn/Trp and L-kynurenine and increases valeric acid production. This process inhibits Tregs and activates T cells and remarkably improves the sensitivity of anti-PD-1 immunotherapy [ 96 ]. Gegen Qinlian decoction enhances the efficacy of anti-PD-1 through its association with glycerophospholipid and sphingolipid metabolism of the microbiota [ 97 ].

Altogether, based on the connection between gut microbiota and TCM, we can develop specific TCM strategies to modulate the intestinal barrier and immunity, and explore the potential for combined treatment with TCM and other cancer therapies.

Chemotherapy and radiotherapy

The efficacy of chemotherapy and radiotherapy is inextricably linked to gut microbiota. Colbert et al. has revealed a correlation between the abundance of gut microbial communities and the clinical outcomes of cisplatin and radiation therapy. Specific gut microbes have been shown to positively influence on the therapeutic effects of chemoradiotherapy [ 16 ].

The interaction among the host, microbiota, and chemotherapy is highly complex. In a vitro experiment, non-pathogenic E. coli or Listeria welshimeri were co-cultured with 30 chemotherapeutic drugs. The outcome revealed that the anti-cancer efficacy of 10 drugs was inhibited by one or both bacterial species, whereas the same bacteria could enhance the efficacy of the other six drugs [ 98 ]. Even different strains of one bacterial species have distinct impacts on cancer treatment. Enterotoxigenic B. fragilis promotes the development of CRC, while non-enterotoxigenic one enhances the efficacy of oxaliplatin [ 15 ]. The genes in E. coli that change the effectiveness of 5-FU have been found in recent Caenorhabditis elegans models. These genes are particularly linked to the metabolism of ribonucleotides and vitamins B6 and B9. When they are muted, the efficacy of 5-FU is consequently diminished [ 99 ]. Beyond influencing the pharmacokinetics of chemotherapy, gut microbiota impacts therapeutic outcomes of chemotherapy through immune regulation. Enterococcus hirae and Barnesiella intestinihominis enhance the sensitivity and responsiveness to the cyclophosphamide (CTX). E. hirae increases the CD8 + /Treg ratio in malignancies when it moves from the small intestine to lymphoid tissues. Meanwhile, B. intestinihominis facilitates the infiltration of IFN-γ-producing T cells into the TME [ 100 ].

Growing evidence suggests that gut microbiota also mediate the heterogeneity of tumor responses to radiotherapy through immune remodeling. Commensal gut microbiota in the mesenteric lymph nodes activates innate immune responses via LPS and enhances the toxicity of CD8 + T cells following total body irradiation (TBI) [ 101 ]. Antibiotic therapy or blocking LPS signaling reduces TBI's capacity to regress tumors [ 101 ]. The depletion of bacterial communities leads to a relative expansion of fungi, the Saccharomycetes expresses inhibitory signals to tumor immunity through the innate sensor Dectin-1, making radiotherapy less effective [ 102 ].

Polymorphic microbiome and tumor therapeutic resistance and toxicity

There is a connection between gut microbiota and the resistance and toxicity of cancer therapies. Polymorphic microbiome is a comprehensive analysis technology that integrates various analytical methods such as microbial metagenomics, metatranscriptomics, metaproteomics, and metabonomics, and combines these technologies with clinical data [ 103 ]. With the advancement of polymorphic microbiome, we are now able to have a deeper exploration into the composition of microbial communities, transcriptional landscapes, protein expression levels, and metabolic differences in cancer. The following section presents a systematical review of the application of polymorphic microbiome in the study of anti-cancer medication resistance and toxicity.

Microbial metagenomics

Through the analysis of the abundance, diversity, and composition of microbiota at the genomic level, metagenomic sequencing technology offers a novel perspective about the structure of microbial communities. It provides platforms for high-throughput platforms for characterizing complex microbial communities and have been extensively applied in both clinical and preclinical researches.

Application of microbial metagenomics in immunotherapy

Only 20–40% of patients respond to ICIs even for the most sensitive tumors [ 104 ]. A multitude of studies have sequenced gut microbial genome of ICI patients. According to the analysis, the better outcomes of ICIs are associated with certain bacterial species, including Alistipes, Akkermansia, Bifidobacterium, Collinsella, Enterococcus, Faecalibacterium, Roseburia, Coprobacter, and Bacteroides [ 18 , 105 , 106 ]. Discrepancies in microbial compositions across studies are caused by differences in sample collection, sequencing, and statistical methods. Interestingly, these bacteria have been shown to participate in the immune remodeling of the TME [ 71 , 106 ]. Recently, FMT has emerged as a heated strategy to overcome resistance to ICIs, with clinical trials indicating its potential to reverse unresponsiveness [ 18 , 21 , 107 ].

A challenge of the broad application of ICIs is the potential risk of immune-related adverse events (irAEs). Colitis is one of the adverse events induced by ICIs. Patients with ICI-induced colitis have been proved to occur characteristic alterations in gut microbiota [ 108 ]. In animal models, mice pre-treated with antibiotics developed nearly fatal colitis following anti-CTLA-4 treatment. However, the pathological response can be significantly reduced through the oral administration of the probiotic Bifidobacterium [ 109 ].

CAR-T, also subjects patients to a range of toxicities, including but not limited to cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome, and fatal macrophage activation syndrome [ 110 ]. A study by Hu et al. found that multiple myeloma patients with severe CRS showed higher levels of Leuconostoc , Staphylococcus , Stenotrophomonas , and Bifidobacterium . However, an increased prevalence of Sutterella has been linked to longer survival and full remission [ 80 ]. Therefore, a comprehensive understanding of gut microbiota is essential for optimizing CAR-T therapy outcomes.

Application of microbial metagenomics in chemotherapy and radiotherapy

Gut microbiota joins in the development of chemotherapy resistance through influencing drug metabolism. A clinical study revealed that bacterial DNA of class Gammaproteobacteria , especially from the Enterobacteriaceae and Pseudomonadaceae families were detected in most PDAC samples. These bacteria express the enzyme cytidine deaminase (CDD L ). The process reduces the localized gemcitabine concentration and mediated the resistance [ 19 ]. Sitthirak et al. demonstrated that Gammaproteobacteria abundance was also dramatically increased in the cisplatin and gemcitabine-resistant groups [ 111 ].

Gut microbiota is an effective biomaker for chemotherapy toxicity. An increase in F. nucleatum and a decrease in Streptococcus and Prevotella have been associated with oral mucositis [ 112 ]. On one hand, the microbial communities directly affect chemotherapy toxicity by influencing drug metabolism. Irinotecan's active form, SN-38, is converted into non-toxic SN-38G in the liver. Bacterial β-glucuronidases in the intestine transforms SN-38G back into SN-38, causing intestinal toxicity [ 113 ]. On the other hand, microbiota indirectly affects toxicity through immunoe remodeling. Bifidobacterium infantis was able to alleviate the toxicity induced by 5-FU and oxaliplatin by enhancing the activity of CD4 + CD25 + Foxp3 + T cells and inhibiting Th1 and Th17 cells [ 114 ]. All in all, selectively targeting gut microbiota holds promise for the future in decreasing the side effects of chemotherapy and improving the quality of life for patients.

Radiotherapy disrupts the mucosal barrier, leading to a shift in gut microbiota. This displacement of the microbial communities further trigger uncontrolled intestinal immune responses, ultimately resulting in the occurrence of radiation enteropathy [ 115 ]. Patients with radiation-induced complications exhibit a reduction in bacterial diversity and an enrichment of specific microbial groups. Ferreira et al. found a positive correlation between the abundance of Phascolarctobacterium , Roseburia , and Clostridium IV and the development of radiation enteropathy [ 20 ]. FMT alleviates gastrointestinal toxicity by increasing the thickness of the mucus layer and restoring the integrity of the intestinal epithelium [ 108 ]. The VSL#3 probiotic formulation, composed of Streptococcus , Lactobacillus , and Bifidobacterium , protects the intestinal mucosa from the adverse effects of radiotherapy [ 116 ]. Overall, metagenomic analysis can not only predict the risk of radiation enteritis but also provide individualized preventive treatment strategies for patients.

Microbial metatranscriptomics and microbial metaproteomics

Microbial metatranscriptomics is an approach that characterizes the diverse RNA populations of the individual bacteria or the microbiota. It serves as a bridge between metagenomics and metabolomics and proteomics [ 112 ]. By converting CRC cells from an apoptotic state to autophagy, F. nucleatum increases chemoresistance in these cells. When CRC cells were co-cultured with F. nucleatum , RNA-seq analysis showed that genes linked to autophagy pathways were more abundant. Subsequent western blot analysis confirmed that F. nucleatum increases the expression of autophagy-related proteins in cancerous colonocytes [ 117 ].

Microbial metaproteomics reflects the characteristics of numerous peptides and proteins, including expression levels, protein–protein interactions, and post-translational modifications [ 118 ]. However, microbial metaproteomics is currently seldom applied, and its potential in understanding the impact of microorganisms on cancer treatment remains to be further explored.

Microbial multi-omics

Microbial metabolomics, a method based on mass spectrometry technology, provides novel insights into how microorganisms influence cancer treatment by quantitatively analyzing the differences in microbial metabolic products. The intricate relationship between cancer drugs and bacteria cannot be fully understood though analyzing single microbial metabolomics. By combining various omics technologies, we can better identify the patterns of resistance and toxicity. In the gemcitabine group, Deinococcus , Pseudomonas , Streptococcus , and L-methionine were found to be negatively correlated. Low amounts of L-methionine may be resulted from Streptococcus transporting L-methionine into the cells via the ABC transporter [ 111 ] . Park's team conducted a multi-omics analysis combining transcriptomics, lipidomics, and serum metabolomics on CRC mice treated with B. bif _K57 and B. bif _K18 plus anti-PD-1 immunotherapy. Integrating all these data, they concluded that certain species of Bifidobacterium may help overcome resistance in ICIs immunotherapy through promoting IFN-γ production on immune cells [ 119 ]. Omics technologies will be employed to integrate the identification of genes, transcripts, proteins and metabolic processes, thereby enhancing cancer treatment efficiency.

Microbiota-directed cancer therapy strategy

Therapies that direct microbiota represent a new area of oncology research. They have achieved remarkable and rapid progress over the past decade. The timeline of the history and evolution of microbiota-directed therapies is summarized in Fig. 3 and Tables 1 and 2 . All of these methods, whether they are untargeted ones enhance the overall composition of gut microbiota, or targeted ones modify the specific microorganism, are being actively and thoroughly investigated (Fig. 4 ). In this section, we will systematically review these strategies, discussing their advantages and limitations, and assessing their feasibility for clinical application. Fig. 3 The timeline of the history and evolution of the clinical translation of the microbiota-directed cancer therapy. A The cross-sectional timeline of microbiota-directed cancer therapy. Discovery: this stage began with accidental clinical observations. Scientists first noticed the associations between microbiota infections and tumor regression, and attempted to use them to regress tumors; Pre-Clinical Exploration: the focus was on basic research, revealing the connections between gut microbiota and immunity and gut homeostasis; Clinical Trials: based on previous research, clinical studies on microbiota-directed therapies (untargeted and targeted inventions) and combination therapies were carried out. However, there are problems of insufficient targeting and regulatory considerations in clinical applications; Precise and Individualized Treatment: the FDA approved the FMT products during this stage, marking the improvement of the regulatory system. As for the lack of targeting, it will be solved with the development of polymorphic microbiome, bioengineering, and targeted interventions. By analyzing the microbiome profiles of patients, and applying targeted interventions based on the analysis, precision medicine can be achieved in the future. B - G The longitudinal timeline of FMT, probiotics, dietary intervention, engineered microbes, phage therapy and nanomedicine-based drug delivery. CRC, colorectal cancer; TLR, toll-like receptor; Lm , Listeria monocytogenes ; UIRN, regorafenib-encapsulating nanoparticle; PNP, plant-derived nanoparticle; CTX, Cyclophosphamide; CpG-ODN, CpG oligonucleotide; M13@Ag, silver nanoparticles assembled on the surface of M13 phage

Table 1 Microbiota-directed clinical trials Year Intervention Purpose Cancer type Primary outcome measures Phase Status Clinical trial Role in translational medicine 2015–2018 Iron diet Evaluate the impact of iron diet on gut microbiota, inflammation, and CRC risk CRC Inflammatory indicators Not Applicable Completed NCT03548948 Early clinical trials using diet to fight cancer 2020–2026 High-fiber diet Investigate how dietary changes impact gut microbiota in patients treated with anti-PD-1 therapy Melanoma Change in gut microbiota II Active, not recruiting NCT04645680 Clinical application of combination therapy 2021–2023 Potato starch supplement Evaluate the safety and practicality of dietary supplement to patients treated with dual ICIs Solid cancer AEs I Completed NCT04552418 Exploration of new strategies for the combination treatment 1958 FMT First attempt to treat pseudomembranous enterocolitis with FMT Enterocolitis Cure rate — Completed [ 120 ] First clinical attempt of FMT 2017–2018 FMT Evaluate the safety and effectiveness of FMT in pouchitis patients Pouchitis AEs I, II Terminated NCT02782325 Attention to the safety of FMT 2018–2024 FMT Improve the efficiency of anti-PD-1 therapy Melanoma ORR II Completed NCT03341143 Beginning clinical trial of the combination treatment 2022–2034 FMT Assess the feasibility, efficacy and safety of FMT to cancer patients who do not respond to ICI therapy Solid cancer AEs; ORR II Recruiting NCT05286294 Clinical focus on patients with immunotherapy resistance 2020–2028 FMT Evaluate the safety of FMT in combination with anti-CTLA-4 and anti-PD-1 therapy RCC ORR I Active, not Recruiting NCT04163289 Exploration of new combination patterns 2023 Polymorphic microbiome Find the clinical relevance between microbiota profile and immune response of patients CRC Microbiota composition and metabolites — Completed [ 121 ] Promotion the application of personalized treatment 2016–2018 Probiotic formula capsule Improve the nutrition and health state of CRC patients CRC Inflammatory indicators Not Applicable Completed NCT03782428 Early clinical attempts 2019–2023 Probiotics: CBM 588 Enhance the efficacy of anti-CTLA-4 and anti-PD-1 therapy RCC Change in Bifidobacterium I Completed NCT03829111 The first few clinical trials of the combination therapy 2019–2023 Probiotics: Live Biotherapeutic Product MRx0518 Strengthen immune responses in anti-PD-1 therapy-resistant patients Solid tumors AEs; clinical benefit I, II Terminated NCT03637803 Focus on patients with ICIs resistance 2025–2026 Novel Probiotic Assess how probiotics influence the microbiota in breast tumors and gut Breast cancer Beta-D-Glucagon; metabolite levels Not Applicable Not yet recruiting NCT04362826 Inspiration for developing more precise probiotics 1890 s Bacteria mix vaccine Attempt to treat patients with inoperable sarcoma Sarcoma DFS; disease progression — Completed [ 122 ] First clinical attempt of bacteria vaccine 2014–2019 Vaccines: CRS-207 Evaluate the anti-tumor response combined with chemotherapy Pleural mesothelioma AEs; immune indicators I Completed NCT01675765 Early clinical applications of bacterial vaccines 2015–2018 Vaccines: JNJ-64041809 Assess the recommended dose of JNJ-64041809 mCRPC DLT; T-cell Response; AEs I Completed NCT02625857 Standards establishment for the clinical application 2017–2023 Engineered Listeria (CRS-207) Evaluate the safety and efficiency of CRS-207 in combination with nivolumab and ipilimumab Pancreas cancer ORR II Completed NCT03190265 Early clinical trials of combination therapy 2019–2022 Engineered Listeria (ADXS-503) Assess the safety and tolerability of ADXS-503 in combination with Pembrolizumab NSCLC AEs; ORR I, II Completed NCT03847519 Exploration of application standards 2021–2024 Engineered Salmonella (TXSVN) Explore the maximum safe dose of TXSVN Multiple myeloma DLT I Completed NCT03762291 Application of precise clinical trials Abbreviations : RCC renal cell carcinoma, mCRPC metastatic castration-resistant prostate cancer, ORR objective response rate, AEs adverse events, DLT dose-limiting-toxicity, DFS disease-free survival, CRC colorectal cancer, NSCLC non-small cell lung cancer Data source: ClinicalTrials.gov

Fig. 4 Strategies based on gut microbiota in cancer treatment. Techniques for manipulating the microbiome include untargeted interventions (dietary interventions, probiotics and prebiotics, and FMT) as well as targeted interventions (phage therapy, engineered microbes, nanomedicine-based drug delivery and OMVs)

Table 2 Preclinical research of microbiota-directed therapy Year Microbiota-targeted interventions Outcome Level of evidence Role in clinical translation Limitations Dietary intervention 1975 High-fat diets [ 123 ] Promoted CRC by affecting metabolites of gut microbiota Mouse models Early evidence of the relationships between diet, microbiota, and cancer Large individual differences; limited patient compliance; difficulties to achieve a balanced intake of nutrients 2009 High-fiber diets [ 124 ] Induced SCFAs production and modulated the inflammatory response Mouse models Early evidence of the benefits of microbiota metabolites 2013 High-fat diets [ 6 ] Promoted the SASPs production and HCC progression Mouse models Connection between diets and inflammation 2021 High-salt diets [ 125 ] Increased the abundance of Bifidobacterium and induced a robust immune response Mouse models Connection between diets and anti-tumor immune 2024 High-fiber diets [ 126 ] Enhanced the efficacy of radiotherapy and alleviated the intestinal toxicity of radiotherapy Mouse models Transition from basic mechanisms to combination treatment Probiotics and prebiotics 1977 Glycopeptides from Lactobacillus [ 127 ] Promoted the necrosis of tumors Mouse models Early connection between specific bacteria and tumor cell death Poor activity and stability; the double-edged sword of activating the immune response; insufficient in deep research on the mechanism 1997 Bifidobacterium [ 128 ] Inhibited the growth of CRC Mouse models Early discovery of the inhibitory effect 2004 LTA and LPS supplement [ 129 ] Exerted a protective effect on intestinal epithelial injury Mouse models From discovery to in-depth mechanism 2005 Bacteroides fragilis colonization [ 130 ] Directed the maturation of immune cells by polysaccharide Mouse models Link between bacteria and immunity 2015 Bifidobacterium Bifidobacterium [ 12 ] Enhanced ICIs efficiency Mouse models Transition from basic mechanisms to combination therapy 2022 Programmable probiotics E. coli [ 131 ] Regulated gut microbiota and protected the intestinal epithelial barrier Mouse models Tansition of precision probiotic 2023 Probiotics E. coli [ 132 ] Transported the radionuclide to the targeted tumor Mouse models New approaches for targeting tumors FMT 1972 Microbiota cultured with the drug [ 133 ] The drugs degraded when they were co-cultured with the human gut microbiota or in conventional mice In vitro and in vivo Early discovery of the impact of the microbiota on drugs Unstable efficacy; donor screening; ethical and regulatory issues; pathogen transmissionLimitationsLimitations 2013 Microbiota depletion [ 134 ] Suppressed the immune system and weakened the response to chemotherapy Mouse models Breakthroughs in basic research 2015 FMT [ 13 ] Bacteroides species enhanced the ICIs efficiency Mouse models Transition to the combination therapy 2025 FMT [ 135 ] Increased tumor-specific immunity and enhanced the sensitivity to chemoimmunotherapy Mouse models Inspiration for precision medicine Phage therapy 1917 Cultured with Shiga bacilli [ 136 ] Lysed the Shiga bacilli In vitro Discovery of phages Drug resistance; immunogenicity; complexity of combination therapy 1958 Cultured with tumor cells [ 137 ] Phages accumulated in tumors and possessed anti-tumor capabilities Cell lines Connection between phages and tumor regression 2006 Cultured with phage-resistant bacteria [ 138 ] Identified the specific proteins involved in the phage-bacteria interactions In vitro Discovery of specificity structural proteins 2019 Phage therapy [ 139 ] Increased the chemotherapy efficiency Mouse models Transition to the combination therapy with phages 2020 Phage therapy: phage targeting F. nucleatum (M13@Ag) [ 140 ] Prolonged the survival of CRC mice in combination with immunotherapy or chemotherapy Mouse models Transition to the precise therapy 2024 Phage therapy: The combination of 4 phages (SNIPR001) [ 141 ] Selectively killed E. coli in the gut and reduced the occurrence of bacteremia Mouse models Promotion of the clinical development of SNIPR001 Engineered microbes 1973 Engineered E.coil [ 142 ] Constructed the first E. coli with a recombinant plasmid In vitro Beginning of genetic engineering technology Biosafety issues; immunogenicity; demand for sophisticated technical requirements 1995 Listeria expressing TAA [ 143 ] Mediated the anti-tumor specific immunity Mouse models Transition to immune activation research 2022 Engineered Lactococcus lactis FOLactis [ 144 ] Activated a powerful anti-tumor immunity Mouse models Breakthrough in multi-dimensional immune activation 2022 Genetically engineered E.coil [ 22 ] Activated the immune response and controlled tumor growth Mouse models Breakthrough of oral tumor vaccines 2025 Engineered bacteria induced by light [ 145 ] Enhanced the antitumor response in tumors with low-immunogenicity Mouse models Transition to the precise therapy Nanomedicine-based drug delivery 1986 Anticancer protein of a specific size [ 146 ] Proposed EPR for the first time Mouse models Discovery of the anti-tumor properties of nanomaterials Difficulties in controlling the release of nanomedicines; biocompatibility of carriers; high research and development costs; great challenges in multidisciplinary integration 2001 Chitosan nanoparticles [ 147 ] Enhanced the ability of Mycobacterium phlei DNA to inhibit cancer cells Cell lines Transition to research about delivery efficiency 2024 Inulin-Based nanoparticle (UIRN) [ 148 ] UIRN upregulated the abundance of probiotics and the level of SCFAs Mouse models Research transition focusing on targeting ability enhancement 2025 Plant-nanoparticles (PNP) [ 149 ] PNP increased the efficiency of anti-PD-L1 therapy by remodeling microbiota metabolites Mouse models Transition to green and economical nanoparticles

Untargeted interventions

Dietary intervention

Cancers are associated with diets. A range of dietary strategies, including high-fiber diets [ 150 ], ketogenic diets [ 151 ], high-salt diets [ 125 ], and high-fat diets [ 6 ], have been studied for their potential to modify gut microbiota composition and influence tumor progression. For instance, high-salt diets have been observed to increase the abundance of Bifidobacterium in the gut and promote its migration to tumor tissues where Bifidobacterium effectively activates natural NK cells and induces antitumor immunity [ 125 ]. In contrast, high-fat diets enhance the occurrence of hepatocellular carcinoma through the promotion of inflammatory cytokine production by HSCs [ 6 ]. Notably, the components of daily diets and the nutritional needs are complex [ 152 ], making it difficult to rely solely on dietary therapy for tumor prevention and treatment in practice. Reasonable dietary strategies must be cautiously formulated in consideration with actual clinical situations.

Probiotics and prebiotics

Probiotics are live microorganisms that have been proven to participate in cancer treatment by maintaining the gut barrier integrity and regulating the immune system. Lactobacillus and E.- coli protect gut epithelium by upregulating tight protein and mucin protein expression. Specific probiotics activate DCs and Tregs, inhibit the activity of Th17, and suppress the expression of inflammatory factors like IL-23 and IL-17 [ 153 ]. CC4, a mixture of four Clostridiales strains, even superior therapeutic effects to anti-PD-1 therapy in a CRC model [ 154 ]. Although probiotics have yielded promising results in animal experiments, this therapy still faces issues such as low gastrointestinal absorption rate and insufficient concentration at the lesion site. Programmed probiotics appear to be a promising avenue for solving these problems. Zhou et al. encapsulated E. coli with a biofilm composed of chitosan and sodium alginate. The shell endows the probiotics with higher bioavailability, biosafety, and absorption rate in vivo. In a mouse model, it demonstrated the ability to regulate gut microbiota and restore the integrity of the intestinal mucosa [ 131 ]. Nevertheless, several other studies have indicated that the application of probiotics not only fails to improve clinical outcomes but also reduces the efficacy of cancer treatments. For instance, orally gavaging B. longum or L GG have been found to impair the effectiveness of anti-PD-L1 [ 150 ]. Future research needs to investigate how to customize probiotic treatment plans according to the different conditions of the hosts.

Prebiotics are indigestible food substances that influence the composition of gut microbiota [ 155 ]. Inulin and pectin, which are naturally contained in many fruits and vegetables, increase the levels of SCFAs in the gut, thus enhancing the efficacy of anti-PD-1 immunotherapy [ 156 , 157 ]. Synbiotics, a combination of probiotics and prebiotics, have shown more positive benefits. Motoori et al. discovered that synbiotics in combination with chemotherapy drugs largely reduced the incidence of chemotherapy-related adverse reactions compared to the use of probiotics alone [ 158 ].

FMT

FMT refers to the process of transferring feces from a healthy donor to a recipient with microbiota dysbiosis [ 159 ]. As previously mentioned, FMT has the potential not only to enhance the efficacy of cancer treatments and overcome resistance but also to alleviate adverse reactions associated with therapy. The transplantation material of FMT is not a simple drug but highly individualized gut microbiotas. It makes FMT particularly challenging to regulate. The FDA has changed its stance on the regulatory issues of FMT many times [ 160 ]. Countries such as India and Finland have not even formulated regulatory procedures for FMT [ 161 ]. FMT is highly dynamic. The therapeutic effects of different clinicals trials are closely associated with donor and recipient selection, sample collection, and the route and frequency of administration. During the Second ROME Consensus Conference, global experts established a standardized pipeline for FMT, providing guidelines to ensure more stable therapeutic effects in its clinical applications. The conference reached consensus in many aspects. For instance, donors are required to receive investigations of their medical history, blood, and feces. And it is recommended to use frozen feces for transplantation procedures to maintain the activity and stability [ 162 ].

Targeted interventions

Phage therapy

Cancer patients often take antibiotics during treatment to prevent infections because of the impaired immune system. However, antibiotics lack specificity may cause more harm than good by reducing the diversity of gut microbiota. In contrast, phage therapy target specific harmful bacteria, minimizing the loss of beneficial commensal microbiota [ 163 ]. For instance, engineered phages targeting E. coli by CRISPR-Cas system effectively reduced the E. coli load in mouse models’ intestines, serving as a strategy to prevent bacterial translocation and bacteremia during cancer therapy [ 141 ]. Dong et al. designed the M13 phage coated with silver nanoparticles (M13@Ag), which targets F. nucleatum , the bacteria that increase myeloid-derived suppressor cells (MDSCs) . It enhances the efficacy of immunotherapy and chemotherapy by reducing MDSCs production and immunogenically activating DCs and promoting the polarization towards the M1 phenotype [ 140 ]. Nevertheless, the practical application of phages faces numerous challenges, including phage resistance, potential immunogenicity, and the complexity of designing the delivery systems. Addressing these difficulties is a focal point for future research.

Engineered microbes

Bioengineering technology makes the possibility of engineering specific microorganisms to exert antitumor effects become a reality (Fig. 4 ). These bioengineered bacterial strains are designed to delivery drugs to specific cells. Guo et al. engineered a kind of Salmonella typhimurium that expresses a cytotoxic agent apoptin. The injection of this bioengineered bacterial inhibited tumor growth and extended the survival time in murine models [ 164 ]. More interestingly, bacteria can be programmed as"intratumoral bioreactors". Cis and trans-gene regulatory elements are assembled in a specific manner in the bacteria to form feedback loops. The modified bacteria do not lyse and release the anticancer medicines into the TME until the bacterial population reaches a specific density. The few surviving cells after lysis begin to proliferate again [ 165 ]. This coordinated cycle, which expands and regresses according to bacterial density, optimizes the medicinal potential of genetically modified bacteria while averting harmful side effects.

Engineered bacteria can also express prodrug-converting enzymes, affecting the metabolism of tumor drugs. Salmonella expresses cytosine deaminase which turns the prodrug 5-fluorocytosine into the toxic form 5-fluorouracil [ 166 ], resulting in tumor regression. Additionally, engineered bacteria can be used to reshape the metabolic and immune microenvironment of tumors. Increased levels of L-arginine help enhance the antitumor capabilities of T cells [ 167 ]. Canale et al. synthesized an E. coli Nissle (EcN) 1917 that colonizes locally in tumors and converts tumor metabolic waste into L-arginine. The bioengineered bacteria synergized with ICIs and enhanced the antitumor response [ 168 ].

Employing engineered microbes as vaccines is an innovative application in oncology. Currently, Lactococcus [ 144 ], Mycobacterium (BCG) [ 169 ], and Escherichia [ 170 ] have been engineered as powerful vectors for anti-infective or anticancer vaccines. Recently, Redenti et al. designed EcN 1917 as a delivery platform for expressing tumor neoantigen peptides. Experimental results indicate that this EcN elicited a strong and long-lasting immune response, successfully inhibiting tumor growth and preventing tumor recurrence [ 170 ]. Most cancer vaccines are administered via subcutaneous or intramuscular injection, which only induces systematical humoral immunity against pathogens, with limited cellular immunity and weak mucosal antibodies [ 171 ]. Oral administration, on the other hand, is a safer alternative that elicits a stronger antitumor immune response. Yue's team designed an"artificial robot", which is basically a modified E. coli . This “artificial robot” releases OMVs loaded with tumor antigens into the intestine through oral administration, generating a specific immune response [ 22 ]. However, engineered microbes, as a type of exogenous antigen, may trigger abnormal immune responses. And the high requirements for biotechnology limit their widespread application.

Nanomedicine-based drug delivery

Compared with normal tissues, solid tumors possess abundant highly permeable neovessels and the imperfect lymphatic drainage system. This characteristic enables nanoparticles to more selectively accumulate in tumor tissues. It is called enhanced permeability and retention (EPR) effect [ 172 ]. Mupirocin-derived nanoparticles have been proven to target the pro-carcinogenic F. nucleatum in tumor tissues without affecting the normal gut microbiota, which reduces the side effects of antibiotic mupirocin [ 173 ]. Song et al. incorporated the coding sequence targeting the LPS protein into the nanodelivery system. The specially designed nanoparticles can not only passively accumulate at tumor tissues by EPR effect, but also actively target these areas mediated by targeting protein. The increased capture of LPS reverses the tumor immunosuppressive microenvironment, improving the efficacy of anti-PD-L1 therapy [ 174 ]. Nanomaterials hold great potential in the medical field. Selecting appropriate nanomaterials to enhance their biocompatibility and adopting suitable methods to control drug release may accelerate the clinical translation process of nanomedicine-based drug delivery.

OMVs

OMVs are membrane sacs released during the growth of gram-negative bacteria [ 175 ]. These vesicles encapsulate a variety of bacterial components, including lipopolysaccharides, enzymes, DNA, RNA, and peptidoglycan [ 176 ]. OMVs are capable of reaching the site of tumors through the body’s fluid circulation, where they induce a robust immune response. Owing to the unique biological properties, OMVs have made remarkable progress in their application for vaccines, adjuvants, immunotherapies, drug delivery systems, and anti-bacterial agents [ 177 ]. Of note, the application of OMVs in tumor treatment is relatively under-developed, and more research is needed to explore their potential.

Challenges and perspective

In this review, we summarized the function of gut microbiota and its metabolites in controlling tumor metabolic reprogramming and reshaping the TME. By presenting findings from animal experiments and clinical trials, we emphasized that gut microbiota enhances the efficacy of current cancer treatment through immune remodeling and drug metabolism. Specific gut microbiota also predicts drug resistance and toxicity in cancer treatment, making them attractive biomarkers for cancer therapy.

However, whether there is merely a correlation or a definite relationship between gut microbiota and oncology remains a problem. Fortunately, increasing research findings have discovered the molecular mechanisms by which gut microbiota directly influences tumorigenesis. A recent study carried out by Chen et al. found that Lactobacillus plantarum MM89-derived γ-Linolenic acid mediates mitochondrial damage in CRC cells, which promotes ferroptosis of tumor cells [ 178 ]. At the genetic level, gut microbiota has been demonstrated to promote the expression of the tumor suppressor gene p53 by inhibiting lncRNA Snhg9. This protective effect reduces the risk of colorectal tumorigenesis under mild inflammatory condition [ 179 ]. In addition, from the perspective of evidence-based medicine, clinical studies have found that there are differences in gut microbiota between patients with different tumors and those in healthy individuals. The differences are observed in patients with tumors such as, but not limited to, CRC, lung cancer, and cervical cancers, etc. [ 180 ]. And studies have found that the composition of gut microbiota is also closely related to the prognosis of tumor treatment [ 181 ].

With the advent of in-depth investigations, microbiota-directed therapy has been shown to be a powerful anti-cancer strategy. It prevents and treats cancer by restoring intestinal homeostasis, strengthening the intestinal mucosal barrier, enhancing immunity, and promoting apoptosis of malignant cells. In recent years, there has been a growing number of clinical studies on FMT, dietary intervention, probiotic and engineered bacteria therapies (Table 1 ). Clinical research data indicate that when microbiota-directed therapy is used in combination with traditional cancer therapies, it significantly enhances the therapeutic effect, reduces the incidence of adverse events, thereby improving patient outcomes. FMT is one of the most mature clinical translations of microbiota-directed therapies. In 2022 and 2023, two FMT products, RBX2660 and SER-109, were approved by the FDA respectively [ 182 , 183 ], validating the clinical value of microbiota-based therapies. Regrettably, compared with untargeted interventions, clinical trials of targeted interventions are currently relatively scarce. Existing research mainly focuses on the biological modification of model strains (Table 1 ).

Microbiota-directed therapy still encounters many difficulties in clinical practice. How to precisely locate the therapeutic targets at the bacterial level stands out as a conspicuous problem. Because weak targeting may disrupt the homeostasis of the microbiota, leading to metabolic disorder and infection. The problems faced in clinical research can provide directions for preclinical research (Table 2 ). The application of bioengineering technologies has offered methods to improve the targeting and specificity of microbiota-directed therapy. Brödel et al. took use of a particle derived from phages to deliver a base editor in situ in gut microbiota. The particle precisely modified the genes in E.coli and achieved long-term stability in the mouse model [ 184 ]. Moreover, the nanomedicine-based drug delivery we mentioned above is a highly effective solution to address the insufficient targeting of microbiota-directed strategies. The latest research published in 2025 has further expanded the application of nanodelivery strategies in cancer treatment. Teng et al. extracted the exosome-like nanoparticles GELN from ginger. The miR159a-3p in GELN specifically targeted bacterial phospholipase C, resulting in the accumulation of docosahexaenoic acid (DHA). The increased DHA inhibited PD-L1 transcription in tumor cells and increased the efficacy of ICIs [ 149 ].

Microbiota-directed therapies also have some other common problems. For example, the sophisticated bioengineering technologies required for targeted interventions limit its clinical translation and large-scale production. We need to optimize the design of delivery carriers, explore simplified bioengineering technologies in microbiota editing, and invent modular engineered bacteria. Modular E. coli represents a highly mature technology. By integrating different functional modules, E. coli has been demonstrated to significantly improve the production efficiency of 5-hydroxytryptophan from the fermentation of glucose [ 185 ]. These efficient modular processes can be introduced into industrial production and be applied to reshape the amino acid energy metabolism in the TME. It may emerge as a potentially valuable and effective anti-cancer strategy in the future. Alternative technologies and low-cost materials should also be explored. Nanomaterials synthesized from natural resources or natural biomolecules are a relatively inexpensive production approach. Compared with some expensive metal nanomaterials, plant-derived nanomaterials are abundant in supply and low in cost. They have also shown their superior delivery properties and should be further explored [ 149 ]. There are more challenges. For example, the therapeutic effect of microbiota-directed therapy is severely affected by the differences in microbiotas among individuals. And the regulation and ethics of these biological products, as well as the effectiveness and safety of long-term application, have not been verified yet (Table 2 ). This reminds us that more research should be carried out to tackle these issues one by one.

Despite these drawbacks, they still exhibit great potential for anti-tumor effects. Microbiota-directed therapy integrating with microbiota profiling, represents a research trend in future precision medicine. Specifically, multi-omics techniques and host genome or epigenome can be employed to analyze the profiles of the microbiota as well as the host. Patient-specific microbiota and metabolites associated with cancer are identified. The composition of gut microbiota is an effective biomarker for treatment response, drug resistance, and prognosis in different tumor treatment. By integrating artificial intelligence and big-data analysis, we can predict the responsiveness and adverse effects of patients and tailor the most suitable strategy for them (Fig. 5 ). Fig. 5 Application of polymorphic microbiome in precision medicine. Fecal, blood, and tumor tissue samples are collected from patients for machine learning. We could combine the analysis of microbial multi-omics (metagenomics, metatranscriptomics, metaproteomics, metabolomics), host genome and host epigenome. These evaluations are used to forecast prognoses and design the best possible treatment plans to improve therapeutic efficacy, overcome drug resistance, and reduce toxicity

In a word, the insufficient targeting and the instability of the therapeutic effect are the two main problems hindering the clinical application of microbiota-directed therapy. Future research should concentrate on developing convenient and low-cost polymorphic microbiome detection technologies, strengthening the collaboration between different disciplines to improve targeting ability and anti-tumor properties, and conducting large-scale clinical trials to further validate the efficiency and safety of the therapy. It will definitely promote the progress of the clinical translation of microbiota-directed therapy in the field of precision medicine.

Publisher’s Note

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

Authors’ contributions

Mengying Cui conceptualized the review paper. Lixuan Wang structured the review. Weibo Jiang & Manshi Yang & Quezhu Danzeng designed the Figures. Lixuan Wang & Weibo Jiang & Quezhu Danzeng & Shiyu Liu contributed major amounts to manuscript writing and revising. Manshi Yang & Quezhu Danzeng & Shiyu Liu surveyed the literature. All authors were major contributors to revision, editing and proof-reading the manuscript. All authors read and approved the final manuscript.

Funding

This study was funded by Natural Science Foundation of China (No. 82303116), Natural Science Foundation of Jilin Province (YDZJ202301ZYTS047) and Health Science and Technology Capacity improvement Project of Jilin Province (2022 JC069).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.

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