Inflammation in cancer: therapeutic opportunities from new insights.

Introduction

German physician Rudolf Virchow first reported the relationship between inflammation and tumors in the nineteenth century [ 1 ]. Chronic inflammatory processes are a fundamental innate immune response to perturbed tissue homeostasis and affect multiple stages of tumor development, including initiation, promotion, malignant conversion, invasion, and metastasis [ 2 ]. It is estimated that 15–20% of tumor-related deaths are linked to inflammation.

Recently, a growing body of evidence from basic research and clinical data indicates that inflammatory molecules and inflammation pathways can promote the occurrence and progression of various tumors. Pro-inflammatory cytokines, like interleukin (IL)−6, IL-1β, and tumor necrosis factor-α (TNF-α), as well as transcription factors, like nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3), are key players in this relationship [ 3 – 7 ]. Encouraged by pro-inflammatory cytokines, NF-κB and STAT3 can control the expression of target genes, the majority of which are carcinogenic, and increase the ability of cancer cells to survive, proliferate, invade, and spread [ 8 – 10 ]. It is now well-acknowledged that chemicals and processes associated with inflammation can be valuable targets for cancer prevention and treatment.

During the past decades, there has been strong epidemiological evidence showing that nonsteroidal anti-inflammatory drugs (NSAIDs), especially aspirin, have been associated with a reduction in the incidence and mortality of a variety of types of cancer with long-term use, especially colorectal cancer (CRC) [ 11 , 12 ]. In 2016, the US Preventive Services Task Force (USPSTF) recommended low-dose aspirin for primary prevention of CRC for adults aged 50–59 years [ 13 ]. Besides, low-dose aspirin or non-aspirin NSAIDs intake is inversely related to gastric cancer risk based on multiple meta-analyses [ 14 – 16 ]. Recent research based on electronic endoscopy [ 20 ] and territory-wide healthcare databases [ 17 ] also verified these results. Except for CRC and gastric cancer, aspirin use also reduces the incidence and mortality of endometrial cancer [ 18 ], breast cancer [ 19 , 20 ], esophageal cancer [ 21 ], liver cancer [ 22 ], and more. Besides, other NSAIDs and steroid anti-inflammatory drugs also have obvious anti-tumor effects. For example, the novel indomethacin derivative CZ-212–3 showed antitumor effects in castration-resistant prostate cancer [ 23 ]; indomethacin sensitized death receptor 5 (DR5)-deficient tumor cells to adoptive T-cell therapy [ 24 ]; indomethacin-loaded nanocapsules treatment reduced glioblastoma growth in a rat model [ 25 ]. These suggest that FDA-approved NSAIDs and steroid anti-inflammatory drugs are promising candidate drugs for cancer prevention and treatment.

In this review, the detailed information on cytokines and their function in tumorigenesis are comprehensively analyzed, and their potential as therapeutic targets for cancer treatment and chemoprevention and their inhibitor/agonists applied in preclinical and clinical studies are also clarified. Uncovering the exact mechanisms of inflammation and inflammatory factors enabled the development of novel, tailored, and highly effective cancer prevention and treatment strategies. We also discussed Food and Drug Administration (FDA)-approved non-anti-tumor drugs that may help prevent and treat cancer-related chronic inflammation, such as aspirin, indomethacin, celecoxib, and other NSAIDs and steroidal anti-inflammatory drugs. The effects of these medicines on proinflammatory cytokines and inflammation-related pathways are addressed, and typical clinical study data are presented. According to data from the current review, agents that target chronic inflammation may have a wide range of applications in the future for the prevention and treatment of cancer.

The relationship between inflammation and cancer

The process of inflammation

Infection, tissue injury, tissue stress, and malfunction are the main causes of inflammation, and they can cause different physiological reactions and pathological outcomes [ 26 ]. The acute inflammatory response is triggered by infection or tissue injury, and the blood components including plasma and leukocytes will be recruited to the site of infection and injury [ 27 ]. A chronic inflammatory state ensues if the acute inflammatory response fails to eliminate the pathogen [ 28 ]. Except for consistent noxious stimuli like pathogens, other causes of tissue damage such as autoimmune responses or undegradable foreign bodies, can also lead to chronic inflammation [ 26 ].

Specialized sensors elicit the mediators of inflammation, which are activated by inducers of inflammation. The mediators, in turn, alter the functional states of tissues and organs (which are the effectors of inflammation). Based on their biological characteristics, the inflammatory mediators can be classified into seven groups, including vasoactive amines, vasoactive peptides, fragments of complement components, lipid mediators, cytokines, chemokines, and proteolytic enzymes.

The cellular and molecular events during inflammation include a series of complex events, from in situ to systemic inflammation throughout the body. When microbes infect the body, an acute inflammatory response occurs, which will be recognized by the innate immune system, and triggered by Toll-like receptors (TLRs) and NOD-like receptors [ 29 ]. The initial recognition of infection is mediated by tissue-resident macrophages and mast cells, causing the production of many inflammatory mediators, including chemokines, cytokines, vasoactive amines, and others [ 30 ]. If the acute inflammatory response cannot clear the antigen, the inflammation process persists, and chronic inflammation occurs. The different effector classes of the T cells can lead to different inflammatory states [ 26 ].

The crosslink between inflammation, the immune system, metabolism and autophagy in cancer

Among the various inflammatory factors that contribute to cancer susceptibility, infection has come to be recognized as a primary cause of inflammation-induced carcinogenesis [ 2 ]. During infection, inflammation is a fundamental innate immune response to perturbed tissues homeostasis, and inflammation associated with tumor development is triggered by many immune cells [ 31 ]. The regulatory influence on the immune system determines whether inflammation exerts anti-tumorigenic or pro-tumorigenic effects. Tumor heterogeneity is shaped immunologically and through immunosurveillance by immunity’s anti-tumorigenic role. Simultaneously, pro-tumorigenic inflammation fosters cancer by suppressing anti-tumor immunity, modifying the TME to a more permissive state for tumors, and directly influencing cancer and epithelial cells to promote tumors [ 32 ]. The factors that determine whether inflammation promotes or suppresses cancer are various. Currently, there are several directions for cancer prevention and treatment by regulating the immune system, including cancer vaccines and armored anti-tumor immune cells, various forms of immunotherapies, anti-tumor antibodies, and biological therapies.

A growing body of research suggests that immune cell functional changes throughout immunological responses are mediated by metabolic reprogramming [ 33 ]. These suggest that immune response and metabolic reprogramming are necessary events during inflammation-induced carcinogenesis. Reprogrammed energy production and biosynthesis and epigenetic metabolic reprogramming occur in inflammation responses [ 34 ]. The immune system exerts anti-tumor effects through immunosurveillance and immunological sculpting of tumor heterogeneity, while inflammation promotes tumor development by blocking immunity and reshaping the tumor microenvironment by regulating multiple signaling pathways and cellular functions [ 32 ].

Eating a diet that meets energy requirements and provides essential nutrients helps maintain a healthy immune system. Both undernutrition and overnutrition are associated with immune dysfunction [ 35 ]. The immune system works in conjunction with the digestive system, where immunomodulatory and inflammatory processes are linked to gut bacteria and micronutrients [ 36 ]. On one hand, people at risk for deficiencies of immune-enhancing micronutrients, such as the military population, are more susceptible to infection due to their nutritional status [ 37 ]. The immune function of soldiers consuming compound nutritional drinks with vitamins and minerals decreased slightly [ 38 ]. On the other hand, overeating can lead to the accumulation of excess body fat and obesity, which creates a chronic inflammatory state and worsens immunological deficiencies [ 36 , 39 ].

Other biological factors, such as aging, also influence immune competence. The immune system undergoes several changes throughout a person’s life, beginning with the developing immune responses seen in newborns and children. This progression continues to an optimal immune function typically observed in teenagers and young adults. However, in older adults, the immune response may decline [ 40 ]. Certain lifestyle factors, including age-specific dietary choices, can worsen age-related changes by influencing and modifying immune function, and in some cases, inhibiting it. Supplements designed for different age groups may provide a solid foundation for optimal immune function. Additionally, age significantly affects how the body responds to vaccines [ 41 , 42 ]. Creating effective vaccine schedules can enhance the advantages of vaccination and increase the immunogenicity of vaccines.

Several transcription factors like NF-κB are central to immune and inflammatory responses [ 43 ]. Metabolic reprogramming occurs in immune cells during inflammatory stages, including energy production biosynthesis reprogramming, and epigenetic reprogramming [ 33 ].

Recent studies support the idea that autophagy, a fundamental biological process in mammals, is crucial for regulating inflammation and plays a significant role in cancer related to inflammation. Autophagy is generally considered a protective mechanism that helps prevent the hyperactivation of inflammatory mediators and the malignancy caused by chronic inflammation [ 44 ]. Defects in canonical autophagy or mitophagy can lead to necrosis and pathogenic responses, which promote cancer and chronic inflammation [ 45 ]. Microorganisms, damaged organelles, and crystals are sources of inflammatory signals, making canonical autophagy an anti-inflammatory process [ 46 ]. Autophagy influences immune cells by regulating mitochondrial and endoplasmic reticulum composition. These metabolic changes lead to immunometabolic states that affect macrophage and T cell polarization, ultimately impacting inflammation [ 47 , 48 ]. The non-canonical autophagy, including LC3-associated phagocytosis (LAP) and its variants, such as LC3-associated endocytosis (LANDO), also utilizes some autophagy machinery and influences inflammation [ 49 ]. Research shows that LANDO’s long-term clearance of beta-amyloid (Ab) aggregates influences the recycling of Ab receptors and reduces inflammation [ 50 ]. When autophagy is inactivated, there is an increased production and secretion of TNFα, type I and type II interferon (IFN), and other inflammatory cytokines [ 51 ]. Autophagy deficiency causes uncontrolled innate immune activation, leading to inflammatory diseases like Crohn’s disease and an increased risk of colon cancer [ 52 ].

Four signaling pathways link autophagy and inflammation in cancer progression: the reactive oxygen species (ROS) signaling pathway, the IκB kinase (IKK)/NF-κB signaling axis, the inflammatory cytokine signaling pathway, and the TLR signaling cascade [ 53 ]. Autophagy-related molecules like UVRAG, IRGM, ATG7, Pink1, and Park2, as well as several receptors, connect autophagy to inflammation and influence inflammation-induced tumors. For example, mice with mutated UVRAG show intestinal inflammation and increased risk of colitis-associated cancer through the NLRP3 inflammasome [ 54 ]. As a key negative regulator of NLRP3 inflammasome activation [ 55 ], immunity-related GTPase M (IRGM) mediates autophagy and enhances cell proliferation in hepatocellular carcinoma with overexpression of AGBL2 [ 56 ]. The activation of ATG7 leads to a pro-inflammatory response dependent on NLRP3, which worsens lipotoxicity in insulinoma [ 57 ]. Mice lacking Pink1 or Park2 are susceptible to Kras-driven pancreatic cancer due to the accumulation of mitochondrial iron and the subsequent activation of the absent in melanoma 2 (AIM2) inflammasome [ 58 ]. FUNDC1 (FUN14 domain-containing 1) is a mitophagy receptor in the mitochondrial membrane that suppresses hepatocellular carcinoma (HCC) initiation by reducing inflammasome activation and inflammation [ 59 ].

As our understanding of the relationship between inflammation, the immune system, metabolism and autophagy in cancer deepens, new therapeutic targets that alter inflammation, the immune system, and metabolism are emerging.

Potential therapeutic strategies for cancer prevention and treatment in inflammation-related cancer

Potential inflammatory therapeutic strategies for cancer prevention and treatment

It is becoming evident that the tumor microenvironment, which is mostly controlled by inflammatory cells, plays a crucial role in cancer development by promoting cell division, survival, and migration. Furthermore, certain innate immune system signaling molecules, including chemokines and their receptors for invasion, migration, and metastasis, have been appropriated by tumor cells. This knowledge is fostering new anti-inflammatory therapy approaches to cancer genesis. Blocking antibodies for inflammatory molecules such as TNF-α has shown obvious therapeutic efficacy in some inflammatory diseases and anti-tumor potential. Matrix metalloproteinases (MMPs) inhibitors have been rapidly developed and applied in the clinic, but the outcomes were less than satisfactory, with efficacy reported mainly occurs during early tumor progression [ 60 ].

Based on epidemiological data and experimental data, the FDA-approved anti-inflammatory drugs exhibit significant anti-tumor effects, suggesting the potential of these drugs as anti-tumor drugs and the targets of these drugs may act as promising targets for cancer prevention and treatment. The molecular mechanism underlying the anti-tumor effect of aspirin was first discovered in the 1970s, and it was demonstrated that it irreversibly acetylates and inactivates the cyclooxygenase (COX) enzyme [ 61 ]. Since the cancer-promoting effect of COX, many COX inhibitors have been synthesized and have the potential as therapeutic drugs in patients with cancer. For example, flurbiprofen suppressed cell proliferation in colorectal cancer [ 62 ], non-small cell lung cancer [ 63 ], and others. While the other anti-tumor mechanisms of NSAIDs represented by aspirin and steroidal anti-inflammatory drugs were partly known. Understanding these processes and molecular mechanisms will provide new targets for the prevention and treatment of tumors. For instance, phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA)/protein kinase B (AKT)/phosphatase and tensin homolog (PTEN), wingless-type MMTV integration site family (Wnt)-β catenin, and NF-κB pathways are signaling pathways that are significantly activated in cancer, patients with mutations of these pathways showed increased survival after using NSAIDs [ 64 ]. Besides, as the important parts of the inflammatory pathway, cytokines, chemokines, growth factors, and components of the extracellular matrix-directed therapy have shown certain effects in anti-tumor treatment. These targets will be summarized in Table 2 .

Potential immune therapeutic strategies for cancer prevention and treatment

As an innate immune response to the imbalance of tissue homeostasis, inflammation affects all stages of the occurrence and development of tumors, including regulating aberrant tissue repair, genotoxicity, proliferative responses, invasion, and metastasis. At the same time, tumors modulate the inflammatory environment through the secretion of soluble growth factors and chemo-attractants, causing inflammatory cells to inhibit the anti-tumor T-cell response [ 2 ]. Moreover, patients with similar illness stages but different racial/ethnic backgrounds or places of residence may exhibit significantly different tumor mutational burdens due to the consequences of exposure to persistent inflammation, which would change the immune system and the biology of tumors [ 65 ]. The complicated interplay of host, tumor, and environmental variables determines immunity and controls the magnitude and timing of the anticancer response. Tumors successfully suppress immune responses by activating negative regulatory pathways (also known as checkpoints) linked by acquiring characteristics that allow them to evade detection actively [ 66 – 68 ]. For various malignancies, immunotherapy is proven to be an efficient therapeutic strategy. Although antibodies targeting the immune regulators CTLA4 and programmed cell death ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) have shown promising therapeutic results, only a small percentage of patients show sustained responses, indicating the need for a more comprehensive understanding of cancer immunity [ 69 ]. A recent study found an interleukin-4 fusion protein (Fc–IL-4), improves the anti-tumor efficacy of immune checkpoint blockade therapies and type 1 immunity-centric adoptive T cell transfer by directly acting on CD8 + T cells and enriching functional terminally exhausted CD8 + T (CD8 + TTE) cells in the tumor, mainly via modification of metabolism mediated by STAT6/mTOR [ 70 ].

Differences in inflammation and immune response lead to cancer disparities, including breast cancer, prostate cancer, lung cancer, colorectal cancer, and more. Cancer risk factors such as obesity, affect individuals with African American (AA) and Latina breast cancer more than those with European American (EA) breast cancer. It causes an inflammatory tumor microenvironment in breast tumors and the growth of pro-tumorigenic crown-like structures (CLSs), which comprise dead adipocytes and activated macrophages [ 71 ]. Increased numbers of tumor-infiltrating macrophages were found in AA patients [ 72 , 73 ]. Increased density of CD8 + T cells was found in AA women and AA women with invasive breast cancer [ 74 ]. Higher immune content score [ 75 ] and difference in the abundance of T-regulatory (Tregs) and T-helper type 2 cells [ 76 ] in AA patients compares with EA patients. Exhausted CD8 T-cells also predict the response to anti-PD1 therapy in ER-positive breast cancer women [ 77 ]. The immune content in breast tumors also relates to the survival of ER-negative breast cancer patients [ 78 , 79 ]. Low-grade inflammation and associated immune cells promote prostate cancer progression [ 80 ]. Several immune cell types such as CD4 + T cells, natural killer cells (NK) cells, and myeloid-derived suppressor cells and elevated release of IL-6 and IL-8 were associated with worse prognosis of prostate cancer patients [ 81 – 85 ]. The increased expression of PD-L2 was linked to poorer distant metastasis-free survival and inferior radiotherapy outcomes either in isolation or in conjunction with radiation therapy, suggesting that it could be a therapeutic target of interest for prostate cancer [ 81 ]. Increased expression of inflammatory factors such as IL-6, vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), Tropomyosin receptor kinase B (TrkB), and higher immune content were found in AA men with prostate cancer [ 86 ]. Moreover, pre-clinical studies showed that immune cells such as Tregs, neutrophils, macrophages, and platelets promote prostate cancer metastasis [ 87 – 90 ]. In lung cancer, the circulating plasma levels of inflammation markers such as IL-6, IL-8, interferon gamma (IFNγ, IL-12/IL-23P40, and C-reactive protein are positively associated with lung cancer prognosis [ 91 ]. Elevated inflammatory mediators were also related to the risk of lung cancer [ 92 ]. IL-15, IL-6, and MCP-4 were identified as potential biomarkers for early-stage lung cancer [ 65 ]. AA CRC has a more immunosuppressive environment than EA CRC patients. AA CRC patients had lower densities of cells labeled with TFNg [ 91 ]. Fewer macrophages and CD8+ T-cells, but more B-cells were seen in AA tumors compared to EA colon cancer [ 93 ]. Therefore, studying how these differences in the immune environment influence tumor biology and exploring the underlying mechanisms may help guide decisions on target therapy. The increased presence of immune-inflammation characteristics in the tumor helps to develop novel treatment therapeutics due to the reason that not every patient can afford the prohibitive expense of immunotherapy.

Although immune checkpoint inhibitors (ICIs) have significant potential, a variety of inflammatory toxicities known as immune-related adverse events (irAEs) have hindered their effectiveness [ 94 ]. ICIs are linked to inflammation and tissue damage in various organs [ 95 , 96 ]. Inflammation also contributes to resistance against ICIs in cases of high microsatellite instability (MSI-H) colorectal cancer [ 97 ]. The reports indicate that reducing inflammation may enhance the effectiveness of immunotherapy. A detailed single-cell analysis of immune cell populations in colitis has identified specific cytokines, chemokines, and surface receptors that could be targeted for therapy. These targets could be beneficial not only for colitis but also for addressing other inflammatory side effects associated with checkpoint blockade, including CXCR6 and CXCL16 [ 98 ]. ICIs and IL-6 antagonists may enhance the antitumoral effect while also reducing the risk of serious adverse events [ 99 ].

Potential metabolic therapeutic strategies for cancer prevention and treatment

Evidence showed that hypercholesterolemia causes cholesterol to build up in immune cells such as macrophages, which in turn triggers inflammatory reactions. These reactions include increased TLR signaling, activation of inflammasomes, and the spleen and bone marrow generation of neutrophils and monocytes. Activation of TLR signaling causes a reduction in cholesterol efflux at the cellular level, which exacerbates inflammatory reactions and causes further cholesterol buildup [ 100 ]. As a key factor that regulates the expression of multiple genes implicated in a wide range of lipid and glucose metabolic pathways, peroxisome proliferator-activated receptor alpha (PPARα) exhibits marked anti-inflammatory capacities [ 101 , 102 ]. It plays an important role in various immune cells such as macrophages [ 103 , 104 ].

As the relationship between metabolic reprogramming and immune cell activation in cancer becomes clearer, novel therapeutic targets are being identified through modifications to immune cells’ intracellular metabolism. Activation of Toll-like receptor (TLR) 4 is a vital factor that induces pro-inflammatory responses and contributes to metabolic syndrome (MetS) [ 105 ]. Therefore, TLRs could be promising targets for the treatment of inflammation-associated diseases as well as cancer.

Studies have shown that PPARα and PPARγ are closely related to carcinogenesis. On the one hand, loss of PPARα promotes the development of colon cancer [ 106 ]. Overexpression of PPARα suppressed HCC development [ 107 ]. PPARγ plays an anti-tumorigenic role in CRC [ 108 ]. On the other hand, PPARα facilitates cell proliferation in prostate cancer [ 109 ]. PPARγ acts as an oncogenic role in the development of thyroid carcinoma [ 110 ]. Several PPAR-interacting miRNAs, such as miR-506 and miR-27a, have been shown to suppress PPARα and PPARγ in cancer cells [ 111 , 112 ]. Besides, the upregulation of PPARs or PPAR agonists has been reported to be involved in chemotherapy resistance by metabolic reprogramming. For example, up-regulated PPARs or PPARs agonists foster chemotherapy resistance in cisplatin-resistant ovarian cancer [ 113 ], hepatocellular carcinoma [ 114 ], colorectal cancer [ 115 ], and NSCLC [ 116 ]. This suggests the potential of PPARs to act as a promising target for cancer treatment and prevention.

Potential antupohagic therapeutic strategies for cancer prevention and treatment

Dysregulation of autophagy contributes to inflammation and tumor progression. Enhancing autophagy can boost CTLA-4 expression and Tregs, potentially reducing inflammation and cancer [ 117 ]. Inhibiting the autophagy pathway encourages the transformation of macrophages into pro-inflammatory M1 cells, which worsens liver inflammation [ 118 ]. Research is focused on small molecules and nanomaterials that modulate autophagy for anti-tumor effects. For example, 3-Methyladenine (3-MA) blocks autophagy, reduces ROS, inactivates pro-inflammatory proteins STAT3 and IL-6, and inhibits the survival of HeLa cells [ 119 ]. Combining the induction of autophagy by rapamycin with the activation of TLR4 and TLR9 has shown to have a synergistic effect in enhancing anticancer effectiveness.

Rapamycin, an autophagy activator, demonstrated enhanced anticancer effectiveness when combined with TLR4/9 agonists in melanoma treatment [ 120 ]. This indicates the potential of combining immunotherapy with autophagy activators for cancer treatment. Besides, GL-V9, an AMPK activator, prevents colorectal cancer associated with colitis by limiting the NLRP3, nucleotide-binding domain leucine-rich repeat (NLR) and pyrin domain-containing receptor (NLRP3) inflammasome through the process of autophagy [ 121 ]. Ergosterol peroxide induces ROS-dependent autophagy and reduces NLRP3 inflammasome activity, inhibiting lung cancer cell migration and proliferation. However, it is still unclear if autophagy directly suppresses inflammasome activity [ 122 ].

Inflammation regulates the hallmarks of cancer

New evidence has strengthened the idea that inflammation plays a crucial role in the development of tumors. Sites of infection, persistent irritation, and inflammation are the origin of many malignancies. It is becoming evident that the tumor microenvironment, which is predominantly regulated by inflammatory cells, plays a crucial role in cancer development by promoting cell division, survival, and migration. It fosters the proliferation of mutant cells and facilitates the spread of malignancy. The hallmarks of inflammation-induced cancer include proliferative and survival signaling promotion, genomic destabilization, angiogenesis promotion, invasion, migration and metastasis induction, and reduced sensitivity of tumors to chemotherapy drugs.

Promoting proliferation and survival signaling

The concept that inflammation enhances cell proliferation has been proposed since 1863, and continuous cell proliferation increases the risk of tumor occurrence [ 1 ]. Various inflammatory molecules, as the main component of the tumor microenvironment, contribute to the proliferation of cancer [ 123 ]. Chronic inflammation results in the continuous release of pro-inflammatory chemokines and cytokines such as interleukins (ILs) 6 and TNFα, as well as transforming growth factor beta (TGF-β), which promote the survival of tumor cells [ 124 , 125 ]. Under the stimulation of inflammatory factors such as IL-6 and IL-1β, NFκB and STAT3 were activated. Then, the expression of various oncogenic genes was dysregulated, promoting cancer cells’ survival and proliferation [ 126 ].

Destabilizing genome

As an enabling characteristic of cancer, genome instability is essential for cancer cell evolution [ 127 , 128 ]. Accurate DNA synthesis and effective DNA repair processes are crucial for maintaining genomic stabilization. Chronic inflammatory processes promote the development of normal cells, their growth, and their transition to malignancy by disrupting cellular homeostasis, producing various DNA damage products, impairing DNA repair pathways, producing an excess of pro-inflammatory cytokines, and lowering the rates at which damaged cells undergo apoptosis [ 129 , 130 ]. Abundant evidence indicates that inflammation contributes to genomic instability [ 131 – 133 ]. Inflammation generates reactive oxygen and nitrogen species (RONS) [ 132 , 134 , 135 ] and ROS [ 136 ] during the inflammatory response, which results in direct DNA damage. The inflammation-associated DNA damage contributes to colon carcinogenesis in mice [ 137 ]. The DNA damage-induced sustained p53 activation contributes to inflammation-associated hepato-carcinogenesis in rats [ 138 ].

Promoting angiogenesis

Angiogenesis is recognized as the process of growth and remodeling that transforms an initial vascular system into the intricate branching network that characterizes adult vasculature [ 139 ]. Anastomosis, migration, survival, proliferation, and ECM breakdown are all part of this intricate multi-step process [ 140 ]. Abnormal vessel growth and function are hallmarks of cancer [ 141 , 142 ]. Abundant evidence showed that in pathological circumstances such as cancer, angiogenesis, and inflammation are closely related [ 143 ]. Various pro-inflammatory chemokines and cytokines released during inflammation are potent activators for endothelial cells (ECs) to attract blood-derived inflammatory cells [ 144 ]. Adhesion molecules play a vital role in this process, and they’re regulated by various pro-inflammatory mediators [ 145 ]. Alternatively, angiogenesis maintains inflammation by providing oxygen and nutrients to meet the metabolic needs of cells at the site of inflammation. The tumor microenvironment is rich in inflammatory molecules such as TNFα, IL-1, IL-6, IL-8, COX-2, and vascular endothelial growth factor (VEGF) [ 146 , 147 ]. For example, as one of the best-characterized inflammatory mediators in carcinogenesis, TNF α activates NF- κ B [ 148 ], which is involved in angiogenesis [ 149 ]. VEGF production contributes to angiogenesis, fostering tumor development [ 150 , 151 ]. Since angiogenesis is essential for the formation and spread of tumors, there were substantial expectations that inhibiting this process would have therapeutic benefits. To demonstrate the utility of anti-angiogenic medicines, more than thirty years and multiple pre-clinical investigations employing a variety of anti-angiogenic strategies were required [ 152 , 153 ]. As one of the most studied targets in clinical trials, VEGF shows significant biological functions [ 154 ]. The first antiangiogenic agent anti-VEGF mAb, has been approved to treat metastasis colorectal cancer combined with chemotherapy [ 155 ]. Anti-inflammatory medications have also been demonstrated to have antiangiogenic properties, suggesting that their use may be advantageous for neoplastic therapy.

Inducing invasion, migration, and metastasis

Inflammatory cells and mediators participate in the invasion, migration, and metastasis of malignant cells. Many cells begin to produce chemokines when they are transforming. As a result, they can use chemokines to help migrate to and survive at locations distant from the original tumor [ 156 – 158 ]. For example, cell migration is influenced by the C-X-C chemokine receptor (CXCR) 4 and its ligand (C-X-C motif) ligand (CXCL) 12 in both healthy and pathological conditions [ 158 ]. Malignant cells often express CXCR4 [ 156 ]. The degree of CXCR4 expression in primary human malignancy is correlated with lymph node metastasis in colorectal, breast, liver, and esophageal cancer [ 159 – 161 ]. Besides, malignant cells from a variety of tissues also express other functional chemokine receptors, such as CX3Chemokine receptor 1 (CX3CR1), CC-chemokine receptor 1 (CCR1), CCR7, CCR9, CCR10, CXCR1, CXCR2, CXCR3, CXCR5, and CXCR7. These receptors are implicated in organ-specific metastasis [ 162 – 167 ]. For instance, the expression of CCR7 is correlated with lymph node metastasis, and CCR9 is correlated with melanoma metastasis to the small intestine. Many of the receptors are expressed by malignant melanoma cells, which could account for melanomas’ high rate of metastasis. Several mechanisms may help malignant cells acquire the ability to express chemokine receptors, including genetic and epigenetic alterations, and autocrine and paracrine extracellular signals. The inflammatory cytokines such as TNF-α, IL-6, and IL-1β, can enhance the invasive ability of tumor cells in ovarian cancer, breast cancer, and others [ 168 – 170 ]. Higher levels of the cytokine IL-6 are associated with increased risk of distant recurrence of HER2-negative early breast cancer [ 171 ]. TGF-β promotes epithelial-mesenchymal transition (EMT) [ 172 , 173 ] and metastasis [ 174 – 178 ] at a late stage of cancer. Inflammatory macrophages contribute to ovarian cancer cell migration in vitro [ 179 ] and ovarian cancer model [ 180 ]. Macrophage-deficient mice could develop tumors but can’t form pulmonary metastasis in a breast cancer model [ 181 ]. In conclusion, malignant cells and invading leukocytes interact with autocrine and paracrine by coordinating chemokines and cytokines. Due to these interactions, malignant cells are more likely to migrate, invade, and survive.

Reducing the sensitivity of tumors to chemotherapeutic drugs, radiotherapy and immunotherapy

Chemotherapy, radiotherapy and immunotherapy are common treatment options utilized for various cancer types. One of the side effects of chemotherapy is producing inflammatory cytokines related to the side effects and drug resistance. Similarly, radiation-induced DNA damage response (DDR) also promotes the release of cytokines and chemokines, which will cause the invasion and metastasis of cancer by triggering the inflammatory process and suppressing the immune function [ 182 , 183 ]. Resistance has been the significant barrier to effective cancer treatment [ 184 – 187 ]. Inflammatory mediators such as GM-CSF, IFN-γ, IL-1β, IL-5, IL-10, and tumor necrosis factor alpha (TNF-α) play crucial roles in the resistance associated with inflammation. For instance, CD4 + T helper 2 (TH2) cells, which are key regulators of inflammatory processes in cancer, can accelerate pulmonary metastasis and promote chemotherapy resistance through the activation of macrophages by IL-4 in breast cancer [ 188 ]. Activated downstream of IL-13, the signal transducer and activator of transcription 6 (STAT6) enhances anti-apoptotic pathways, potentially leading to resistance against cytotoxic CD8 + T cells and chemotherapy in breast cancer [ 189 , 190 ]. NF-κB upregulates the Wnt family member Wnt16B, which attenuates the effects of cytotoxic chemotherapy in prostate cancer [ 191 ]. NF-κB can also be activated by chemotherapy drugs such as paclitaxel, cisplatin, doxorubicin, and bleomycin [ 192 ]. Therefore, inhibition of the inflammatory cytokines pathway and related molecules seems to be an up-and-coming method to improve chemotherapy efficacy. Phytochemicals such as resveratrol, curcumin, genistein, epigallocatechin-3-gallate (EGCG), lycopene, thymoquinone, quercetin, capsaicin, and other phytochemicals, that inhibit the NF-κB pathway have a preventive effect on drug resistance [ 193 – 196 ]. For example, resveratrol enhances doxorubicin-induced cytotoxicity in chemo-resistant B16 melanoma [ 197 ]. Curcumin can sensitize tumors to many chemotherapeutic drugs in various types of cancer, such as colon, breast, liver, lung, ovarian cancer, and others; curcumin also sensitizes tumors to gamma radiation in multiple types of cancer, such as colon cancer, cervical carcinoma, glioma, neuroblastoma, epidermal carcinoma, prostate cancer, and others [ 198 , 199 ].

Radiation kills cancer cells via various mechanisms, while the dying cells promote the release of several cytokines, such as TGF-β [ 200 ]. TGF-β closely relates to radio-resistance by suppressing the immune system and regulating angiogenesis, invasion, and DNA damage [ 201 , 202 ]. Inhibition of TGF-βRI can reverse the radio-resistance of irradiated cells [ 203 ]. In some clinical trials, TGF-β antagonists such as fresolimumab and LY2157299, have been applied to cancer patients undergoing radiotherapy and have obtained some promising results [ 201 ]. For example, TGF-β blocking antibody fresolimumab increases the overall survival of metastatic breast cancer patients [ 204 ]. These suggest that anti-TGF-β medications and radiation therapy together may improve tumor response and minimize side effects. Additionally, LIF mRNA, which is expressed in immune cells such as T-cells, macrophages, and monocytes, as well as in epithelial carcinoma cells and adjacent stromal cells, promotes radio-resistance in nasopharyngeal carcinoma by activating the mTORC1/p70S6K pathway [ 205 ]. The blockade of LIF altered macrophages, slowed tumor progression, and improved the effectiveness of anti-PD-1 therapies in colon cancer [ 206 ].

EMT is an important step during resistance [ 207 ], IL-6 cytokines can promote EMT by activating transcription factors such as STAT3 and Snail. This suggests that blocking IL-6 family cytokines may enhance the effectiveness of immunotherapy. Drugs that target IL-6 cytokines have been shown to improve the efficacy of immune checkpoint blockade (ICB) and reduce irAEs. Several clinical trials are currently underway to evaluate the combination of anti-IL-6 therapies with immunotherapy in cancer treatment [ 208 ]. In animal models of cancer, the upregulation of CD38 is associated with acquired resistance to anti-PD-L1 treatment. CD38 decreases the activity of CD8 T cells and reduces the effectiveness of anti-PD-L1 immunotherapy by contributing to the accumulation of adenosine in tumors [ 209 ]. Blocking CD38 made tumors more susceptible to anti-PD-L1 therapy. Moreover, inhibiting CD39’s enzymatic activity leads to the depletion of intra-tumoral macrophages, modifies the inflammatory response, boosts T cell proliferation, and overcomes anti-PD-1 resistance in colon cancer [ 210 ]. Inhibition of A2A adenosine receptor increases the efficacy of anti-PD-1 and produces T cell-dependent anti-tumor activity in breast and colon cancers [ 211 ]. Inhibition of the CD39-CD73-adenosine axis appears to be a promising strategy for overcoming resistance to immunotherapy.

The relationship between inflammatory diseases and cancer

Crohn’s disease (CD) and ulcerative colitis (UC) are two types of inflammatory bowel disease (IBD) that involve chronic inflammation of the gastrointestinal tract. Patients with Crohn’s disease and ulcerative colitis are at a higher risk of being diagnosed with cancer compared to the general population [ 212 ], such as colorectal cancer [ 213 ], small-bowel cancer [ 214 ], colon cancer [ 215 ], and also the skin cancers, lymphomas and cervical abnormalities [ 216 ]. CD also increases the incidence of anal cancer and anorectal cancer [ 217 ]. The risk of cancer may depend on the severity and duration of inflammation. Pro-inflammatory cytokines such as IL-6, generated during gut inflammation, play a crucial role in cancer development by activating intracellular transcription factors like STAT3 and NF-κB [ 218 ]. Anti-tumor necrosis factor therapy at an intensified dose is the most effective medical treatment for perianal Crohn’s disease, as it can lower the risk of anal tumors [ 219 ].Current data indicates that immunosuppression for IBD does not increase the risk of new or recurrent malignancies [ 220 ]. The blockade of IL-23 using neutralizing antibodies, which has been tested in clinical trials for Crohn’s disease therapy, is anticipated to be an effective method for treating colon cancer and colorectal cancer. This expectation is based on the regulatory role of IL-23 in carcinogenesis [ 215 ].

Aside from IBD, autoimmune diseases like rheumatoid arthritis (RA) and celiac disease are notable. Patients with RA have an increased risk of developing prostate cancer [ 221 ], lung cancer [ 222 ], nonmelanoma skin cancer (NMSC) [ 223 ], and non-Hodgkin’s lymphoma [ 224 ]. Additionally, RA increases the risk of lymphoid, myeloid, cervical, and oropharyngeal cancers, while decreasing the risk of endometrial and colorectal cancers, according to a study of one million women [ 225 ]. Long-term immunological dysregulation, such as altered B cell activation and survival, along with the inflammatory reactions associated with RA development, may further increase the risk of developing cancer [ 226 , 227 ]. Antagonists of TNF-α, Janus kinase (JAK), and IL-6 are commonly used therapeutics for RA, but their effects on tumor development are mixed. For instance, while TNF inhibitors have been found to increase the risk of NMSC in patients with RA, they can also reduce tumor size and metastasis in cases of colorectal and colon cancer [ 228 , 229 ]. JAK inhibitors didn’t increase the risk of cancer [ 230 , 231 ]. Celiac disease is an autoimmune disorder that primarily affects the small intestine and is triggered by gluten consumption in genetically predisposed individuals [ 232 ]. The development of coeliac disease involves a complex immune response to gluten proteins. Celiac disease also increases the risk of non-Hodgkin lymphoma [ 233 ], small bowel carcinoma [ 234 ]. Additionally, it raises the mortality rate among cancer patients [ 235 ].

The gluten-free diet is the primary treatment for coeliac disease. It helps reduce damage to the small intestinal mucosa caused by repeated gluten ingestion, thus lowering the risk of lymphoproliferative malignancies [ 236 ]. Nutritional support, pharmacological agents, and autologous hematopoietic stem-cell transplantation are also recommended for non-responsive type 2 cases [ 237 ]. Additionally, utilizing new techniques such as gene silencing (e.g., RNA interference) or gene editing (e.g., CRISPR-Cas9) to reduce immunogenic gluten proteins could enhance the quality of life for individuals on a gluten-free diet [ 238 ]. A pilot study indicated that a low-gluten RNA interference wheat line did not provoke an immune response after a short-term oral challenge in patients with treated coeliac disease [ 239 ]. These methods may also offer innovative approaches for the primary prevention of celiac disease.

The role of inflammation in certain types of cancer

Several types of tumors are directly related to inflammation. For example, the development of colitis and colitis-associated tumors is closely related to chronic inflammation [ 240 ]. There are several pathogens that play an important role in inflammation-related tumors such as cervical cancer, gastric cancer, and liver cancer. For example, human papillomavirus (HPV) is a major risk factor for the development of cervical cancer, as its proteins are involved, either directly or indirectly, in inflammation that can lead to the onset of this disease [ 241 ]. Immune cell infiltration and the increased secretion of inflammatory cytokines are two primary factors in the development of cervical cancer [ 242 ].

Helicobacter pylori (H. pylori) is classified as a Group I carcinogen and infects over half of the world’s population. It has unique properties that allow it to colonize the gastric epithelium in acidic environments. Infections caused by H. pylori can lead to chronic gastritis, which may progress to severe gastrointestinal conditions, including gastric cancer [ 243 ]. Understanding the complex bacterial virulence mechanisms and their interactions with the host immune system and environmental factors is crucial for comprehending the pathophysiology of H. pylori infection.

In China, the hepatitis B virus (HBV) is the primary cause of liver cancer [ 244 ]. While liver cancer is primarily caused by hepatitis C virus (HCV) infection in South Korea and Japan [ 245 ]. Chronic infections of HBV or HCV, along with factors such as nonalcoholic fatty liver disease (NAFLD) and excessive alcohol consumption, lead to liver injury, chronic inflammation, and ultimately liver cancer [ 246 ]. The transformation of inflammatory tumors in the liver is a gradual and dynamic process [ 247 ]. The chronic inflammation leads to an altered immune environment, increased secretion of inflammatory factors, and dysfunctional NK cells, ultimately resulting in liver cancer [ 248 ].

The role of patient-specific factors in inflammation-related cancer

Various patient-specific factors, such as the microbiome and genetics, play crucial roles in cancer related to inflammation.

The role of microbiome in inflammation-related cancer

The microbiome can influence key characteristics of cancer, including the promotion of harmful local inflammation that contributes to the development of tumors. For instance, Helicobacter pylori colonizes the human gastric mucosa, leading to chronic inflammation and resulting in gastric ulcers, which can eventually progress to stomach cancer [ 243 ]. Research has shown that Fusobacterium nucleatum in colorectal cancer activates NF-κB, an important modulator of inflammation associated with cancer, through its binding to Toll-like receptors and nucleotide-binding oligomerization domain-like receptors [ 249 ]. Moreover, the carcinogenic potential of gut bacteria results in increased production of IL-6 and TNF, activation of STAT3, and activation of the IL-17–IL-23 pathway [ 250 ]. Innate and adaptive host immune responses triggered by microbiota can collaborate to promote the development and spread of malignancies by inducing inflammation that supports cancer growth and increases resistance to cell death.

The composition of microbiota can significantly influence the effectiveness and side effects of cancer treatments, as well as the quality of life after cancer therapy [ 251 ]. For example, there is a significant difference in the microbiome composition between responder and non-responder patients undergoing anti-PD-1 immunotherapy [ 252 , 253 ]. The altered gut microbiome due to antibiotics reduced the effectiveness of ICIs in advanced cancer patients [ 254 ]. Moreover, the effectiveness of chemotherapeutic drugs can also be influenced by bacteria, affecting their metabolism and absorption [ 255 ]. Probiotics and microbiota transplants may be effective strategies for modifying the microbiome, potentially enhancing cancer therapy responses and improving quality of life. For instance, oral supplementation with A. muciniphila or Bifidobacterium can boost the effectiveness of PD-1 or PD-L1 immunotherapy in mouse models of melanoma and lung cancer [ 254 , 256 ]. Importantly, certain probiotic strains, prebiotics like inulin and fructo-oligosaccharides, and synbiotics can reduce gastrointestinal side effects in cervical cancer patients. They do this by altering key metabolic pathways and inflammation, lowering oncogene activity, and ultimately reducing cancer progression [ 257 ]. Microbiome-regulating agents are relatively safe, making them potential adjuvants in clinical cancer treatment and paving the way for personalized therapies. However, more high-quality clinical trials are urgently needed.

The role of genetics in inflammation-related cancer

Cancer was once thought to be solely hereditary, but it is now understood to be influenced by a combination of dysregulated genetic and epigenetic pathways [ 258 ]. Genetic alterations are essential for cancer development and the creation of an inflammatory microenvironment, linking inflammation and cancer through an intrinsic pathway [ 259 ]. Genetic alterations, including oncogene activation through mutations, chromosomal rearrangements, or amplifications, as well as inactivation of tumor-suppressor genes, contribute significantly to cancer development. Among the most frequently mutated dominant oncogenes in human cancer are myelocytomatosis oncogene (MYC) and rats arcomaviral oncogene homolog (RAS), which induce tumor-promoting inflammatory mediators that play critical roles in tumor growth and angiogenesis [ 260 , 261 ]. The Kirsten rats arcomaviral oncogene homolog (KRAS)-G12D mutation promotes immunosuppression and increases resistance to anti-PD-1/PD-L1 immunotherapy in non-small cell lung cancer (NSCLC) [ 262 ]. MYC promotes resistance to immunotherapy and IFNγ by downregulating JAK2 [ 263 ]. Targeting dysregulated MYC or RAS may enhance immunotherapy effects, as several studies have demonstrated. For instance, inhibiting MYC increased tumor immune cell infiltration and made tumors more responsive to anti-PD1 immunotherapy [ 264 ]. OmoMYC, a peptide and mini-protein that inhibits MYC, is currently being developed for evaluation in clinical trials for relapsed or refractory acute myeloid leukemia [ 265 ]. Currently, several inhibitors targeting RAS and MYC mutations are in clinical use or undergoing clinical trials. This offers a promising strategy to enhance anti-tumor effects and overcome the drug resistance of immunotherapy. Additionally, tumor-suppressor proteins like von Hippel-Lindau (VHL) and PTEN can regulate the production of inflammatory mediators [ 266 , 267 ].PTEN treatment improves anti-PD-1 efficacy in mice and reverses the immune-suppressive phenotype of primary tumor-associated macrophages derived from patients [ 268 ]. Administering PTEN externally may serve as a promising cancer immunotherapy strategy.

Targeting inflammatory pathway for cancer chemoprevention

A growing tumor’s inflammatory component may involve various leukocyte types, such as neutrophils, dendritic cells, macrophages, eosinophils, mast cells, and lymphocytes. These leukocyte types can produce a wide range of cytokines, as well as cytotoxic mediators like reactive oxygen species, serine and cysteine proteases, MMPs, and membrane-perforating agents, as well as soluble mediators of cell death like TNF-α, interleukins, and IFNs [ 269 ]. The detailed information about the inflammatory cells and molecules they secret are summarized and shown in Fig. 1 . And the pro- or anti-tumor effect of these inflammatory molecules are also summarized and shown in Fig. 2 and Fig. 3 . TNFα antibodies or inhibitors such as infliximab are undergoing phase 2 clinical trials in breast and renal cell cancer [ 270 ]. Chemokine receptor antagonists like bicyclam plerixafor are now in clinical use in non-Hodgkin lymphoma and multiple myeloma [ 271 ]. Trabedtedin as the cytotoxic drug to tumor-associated macrophages and circulating monocytes, has been used to treat soft-tissue sarcoma and ovarian cancer [ 272 ]. Fibroblast plays an important role in tumor development, and inhibitors of the fibroblast growth factor receptor have been studied in various tumors [ 273 ].

Targeting interleukins for cancer chemoprevention

As the means of communication for immune cells and non-immune cells, interleukins play important roles in the occurrence and development of tumors. Their importance as a target and therapeutic agent is demonstrated by the growing number of clinical trials that are presently ongoing. While the results of clinical trials are not satisfactory. Interleukin-6 monoclonal antibodies have been studied in phase 2 and 3 clinical trials in ovarian and renal cancer [ 274 ]. Anti-interleukin-6 receptor antibody-like tocilizumab successfully treats cachexia in lung cancer patients [ 275 ]. Treated with IL1R antagonists enhances the antitumor effect of gemcitabine and 5-fluorouracil [ 276 ]. More details regarding the function of interleukins and underlying mechanisms in cancer are provided in Table 1 .

Activating interferons for cancer chemoprevention

As the most effective and widely distributed family of cytokines, IFNs are induced by nucleic acids and related to immunity and vascular. IFNs are composed of type I, II, and III IFNs. Type I IFNs include IFN-α, β, ε, κ, and ω; type II IFNs refer to IFNγ; type III IFNs include IFNγ1, FNγ2, FNγ3 (first called IL-28A, IL-28B, and IL-29) [ 277 ]. After stimulation, they are produced and secreted by body cells, such as T lymphocytes, B lymphocytes, macrophages, fibroblasts, and epithelial cells [ 278 ]. All IFNs activate the transcription of interferon-stimulated genes through the Janus kinase (JAK)/STAT pathway. Generally, JAK1 and JAK2 are activated by type II IFN signaling to cause STAT1 homodimerization, whereas TYK2 and JAK1 are activated by type I and III IFN signaling to cause STAT1-2 heterodimerization and IFN-stimulated gene (ISG) factor 3 (ISGF3) creation [ 277 ]. IFNα and IFNβ, which belong to type I interferons, directly control the transcription of over 100 downstream genes, resulting in direct (on cancer cells) and indirect (through immune effector cells and vasculature) effects on tumors [ 278 ]. Drug development and patient assessment of interferon-directed therapies have benefited from new understandings of the endogenous and external activation of type I interferons in the tumor and its microenvironment. Modulation of the interferon system may further reduce cancer morbidity and death when paired with other efficacious cancer treatment methods or with previous observations. Clinical trials were started by the Finnish National Red Cross and Hans Strander and Kari Cantell using partially purified IFNα, which was made from human blood donor leukocytes in Cantell’s Helsinki laboratory [ 279 ]. Abundant evidence indicated the anti-tumor effects of leukocyte-derived INFα on various metastasis solid tumors and hematological malignancies [ 280 ]. Recombinant INFα2 was the first human immunotherapeutic approved by the FDA for cancer [ 281 ].

However, exogenous INFα2 and IFNβ also lead to systemic adverse effects. The discovery of the molecular and cellular aspects of pathways of induction and action of interferon, such as effects of protein products of interferon-stimulated genes (ISGs), cellular actions of interferons, and endogenous nucleic acid-induced pathways, which may provide new opportunities for enhancing the anti-tumor effect of these cytokines. For example, it has been suggested that RNA is a more powerful transcription inducer of interferons regarding RIG-I (retinoic acid-inducible gene I) or Toll-like receptors (TLR3, TLR7, and TLR8). A TLR3 agonist ARNAX facilitates the effect of immunotherapy on patients [ 282 ]. TLR 3 and 7 agonists induce a hot triple-negative breast cancer immune environment [ 283 ]. TLR7/8-agonist-loaded nanoparticles promote the polarization of tumor-associated macrophages to enhance cancer immunotherapy [ 284 ]. Besides, cytoplasmic protein cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS) binds to DNA and initiates the synthesis of cGAMP, activating the stimulator of interferon genes (STING), then activates the endogenous interferon system [ 279 ], which provides a fresh understanding of how immune effector cells’ endogenous interferon system is activated. And the cGAS-STING pathway plays a fundamental and vital function in identifying immunogenic cancer cells. When the intracellular STING protein is activated, various immunostimulatory molecules are produced, which can lead to the maturation of dendritic cells, the polarization of anti-tumor macrophages, the priming and activation of T cells, the activation of natural killer cells, vascular reprogramming, and/or the death of cancer cells. These processes can result in the immune system eliminating tumors and producing anti-tumor immune memory [ 285 ]. STING inhibits the reactivation of dormant metastasis in lung adenocarcinoma [ 286 ]. STING agonist promotes CAR T cell trafficking and persistence in breast cancer [ 287 ]. cGAS-STING-mediated type I interferon signaling enhances the development of stem cell-like CD8 + T cells by inhibiting Akt activity [ 288 ]. The combination of STING agonists with radiotherapy or chemotherapy can enhance the antitumor effect and reduce the side effects caused by conventional treatments [ 289 , 290 ]. Moreover, co-administering STING agonists with CTLA4 and PD1 antibodies demonstrated a significant survival advantage in a preclinical model of HPV + oral tumors [ 291 ]. The combination of the STING agonist DMAXX and CAR T cell therapy significantly increases the number of CAR T cells [ 287 ]. Recent studies have improved our understanding of the cGAS/STING pathway in cancer treatment, but prolonged STING activation can promote carcinogenesis. Analysis of the TCGA database shows that several cGAS-encoding genes are significantly upregulated in malignant tissues compared to normal controls, indicating that cGAS/STING signaling may be active in these cancers [ 292 ]. Current research indicates that STING can increase the expression of the immune checkpoint indoleamine-2,3-dioxygenase (IDO), which may directly or indirectly reduce T-cell function and numbers, thereby promoting immunological escape [ 293 ]. The enzyme cGAS, found in mitochondria, suppresses ferroptosis and promotes the progression of hepatocellular carcinoma [ 294 ]. These reports suggest that cGAS may be a potential target for cancer interventions. The inhibitory effects of astin C, a novel STING-specific inhibitor, on Trex1/BMDMs highlight the potential of astin C for cancer treatment [ 295 ]. Further research is necessary to evaluate the effectiveness of cGAS-STING pathway inhibition in cancer treatment.

The role of IFNs in cancer is complex, based on the time, cells present, total IFN-I signal levels, and the IFNα/β sub-types mediating the effects, frequently producing different results. Additionally, it’s becoming evident that the timing of IFN-I delivery or blockade can have radically different outcomes, illuminating the complex biology at play. More details regarding the function of TLRs and STING and the role of their agonists in cancer are provided in Table 2 and Table 3 respectively.

Targeting TNFs for cancer chemoprevention

In the late 1970s, macrophages were discovered to create a cytokine called TNF, also known as TNFα, which can inhibit tumor cell growth and cause tumor regression [ 296 ]. Lymphotoxin, derived from lymphocytes, has a 50% homologous amino acid sequence and binds to the same receptor with TNFα, it came to be called TNFβ [ 297 ]. The TNF superfamily, composed of 19 ligands and 29 receptors, participates in multiple biological functions. Since their role in inflammation, apoptosis, proliferation, invasion, angiogenesis, metastasis, immune, and others, TNF superfamily members were promising targets for drug development. Numerous investigations showed TNF superfamily members to be a kind of strong inflammatory cytokines that both stimulate complicated immune responses and have anti-tumor properties. TNF superfamily actions can be both advantageous and dangerous. On the one hand, TNF acts as the major mediator of cancer-related inflammation, and many antagonists against the TNF family and their receptors have been approved by the FDA, and some of these are already undergoing clinical testing. For example, anti-TNF treatment (infliximab) enhanced the effects of chemotherapy in colon cancer treatment [ 298 ]. On the other hand, TNF can cause cancer cell death, which makes it a possible cancer therapy. As the first cytokine to be employed for cancer treatment, TNFα has been used in the clinic for the treatment of soft tissue sarcoma [ 35 ] and melanoma [ 36 ]. However, reducing TNF’s toxicity is a major task before TNF can be administered consistently. The advancement of TNF-α therapy in the future will depend on reducing systemic therapy’s toxicity and raising TNF-α dosages to increase the direct tumor response. On the other hand, through indirect tumor effects, the use of innovative modes of action may improve safety and efficacy. More details regarding the function of interleukins in cancer are provided in Table 4 .

Targeting colony-stimulating factors for cancer chemoprevention

The ability to produce in vitro colonies of mature myeloid cells from bone marrow precursor cells after the proliferation and differentiation of these cells was the initial defining characteristic of granulocyte/macrophage colony-stimulating factor (GM-CSF; also known as CSF2), macrophage colony-stimulating factor (M-CSF; also known as CSF1), and granulocyte colony-stimulating factor (G-CSF; also known as CSF3). As the main regulators of granulocyte and macrophage populations, CSF can mobilize stem cells to peripheral blood in sufficient quantities for transplantation, speed up the regeneration of protective white blood cells damaged by chemotherapy, boost anticancer immune responses, and possibly contribute to the development of myeloid leukemias [ 299 ]. More details regarding the function of colony-stimulating factors in cancer are provided in Table 5 .

Targeting chemokines for cancer chemoprevention

Chemokines are 8–12 kDa proteins that are released and bind to Gai-protein-coupled seven-transmembrane-spanning receptors (GPCRs), also known as classical chemokine receptors, to control directed cell movement (chemotaxis), adhesion, cell orientation, and cell–cell interactions [ 300 ]. Comprising around 50 chemokine ligands, 20 signaling GPCRs, and 4 ACKRs, the chemokine system is crucial for various pathological processes. Cancer cells, tissue-resident cells, and recruited immune cells that express a wide variety of chemokine ligands and chemokine receptors all influence the process of carcinogenesis. Chemokines govern the invasiveness, proliferation, and stem-like characteristics of tumor cells. They also influence neoangiogenesis, neurogenesis, and fibrogenesis in stem cells [ 301 ]. Chemokines play a crucial role in guiding immune cell movement when mounting and subsequently delivering an efficient anti-tumor immune response [ 300 ]. Meanwhile, chemokine systems also contribute to pro-tumorigenic immune responses by controlling immune cells’ location and cellular interactions in lymphoid organs and the tumor microenvironment (TME). Chemokines have been attractive therapeutic targets because of their role in mediating the recruitment of anti-tumorigenic immune cells and supporting their activity within TME. Similarly, inhibiting chemokines that draw in and support immune cells’ suppressive roles is an intriguing avenue for future research to enhance treatment outcomes. Additionally, another therapeutic approach being investigated to enhance responses to cancer therapy is the activation or transduction of chemokine receptors on adoptively transferred anti-tumor T cells, which facilitates their ability to enter deeply into the tumor and license their functioning. Significant advancements in our comprehension of the immune system’s function during carcinogenesis have resulted in the creation of innovative immunotherapeutic methods for treating diverse tumors, which have substantially aided cancer patients. Immunotherapy continues to be one of the most promising medical advancements of the twenty-first century. More details regarding the function of chemokines in cancer are provided in Table 6 .

Targeting inflammasomes for cancer chemoprevention

As the innate immune system receptors and sensors, inflammasomes are multiprotein complexes, which react to recognized indicators of endogenous (linked to cellular damage, ATP, ROS, and DNA) and external (related to infections) stimuli [ 302 ]. Inflammasome components include the NACHT, leucine-rich repeat (LRR), and pyrin domain (PYD) domain-containing protein 1 (NLRP1), nucleotide-binding domain leucine-rich repeat (NLR) and pyrin domain-containing receptor (NLRP3)( (also known as cryopyrin), NLR family caspase activation and recruitment domain-containing protein 4 (NLRC4), NOD-like receptor family pyrin domain containing 6 (NLRP6), and absent in melanoma 2 (AIM2). Detailed information on the structure of NLRP1, NLRP3, NLRP4, NLRP6, and AIM2 are shown in Fig. 4 . Their products like interleukin 1β and interleukin 18, along with the adaptor, apoptosis-associated speck-like protein containing caspase activation and recruitment domain (ASC) and the effector caspase-1 both play a major role in carcinogenesis [ 303 ]. The sensor protein on each type of inflammasome determines whether a form of the inflammasome is present by identifying pathogenic ligands and triggering the assembly of inflammasomes. NLRs convert the biologically inactive pro-IL-1beta and pro-IL-18 into their active forms through caspase-1 [ 304 ]. Genetic mutations in NLRP1, NLRP3, NLRC4, and AIM2 are linked with the development of auto-inflammatory diseases, enterocolitis, and cancer [ 305 ]. It is commonly known that inflammatory proteins and their byproducts have a role in developing several cancers, such as skin cancer [ 306 ], lung cancer [ 307 ], and others. Inflammasomes play both protective and detrimental roles in cancer. On one hand, mice that lack NLRP3, ASC, or caspase-1 exhibit increased susceptibility to colitis and to colitis-associated colorectal cancer induced by the chemical colitogen dextran sulfate sodium (DSS) [ 308 , 309 ]. Infusion of recombinant IL-18 reduces tumor frequency in mice deficient in inflammatory components following azoxymethane (AOM) and DSS treatment [ 308 ]. IL-18 plays a role in repairing the epithelial barrier and preventing damage [ 309 ]. This may clarify the protective roles of NLRP3 and IL-18 in relation to colitis-associated colorectal cancer. Mice that lack IL-18 are more vulnerable to developing lung metastasis [ 310 ]. Mice that were injected daily with recombinant IL-18 for five days exhibited fewer lung metastases [ 311 ]. Other NLR sensors, such as NLRP6 and NLRP1b, have also shown protective effects against tumorigenesis. For instance, the NLRP1b inflammasome mediates the secretion of IL-1β and IL-18 in stromal colon cells, providing protection against colon tumorigenesis [ 312 ]. NLRP6 protects against chemical-induced colon cancer by activating caspase-1 and promoting IL-18 production in the intestine [ 313 ]. The blockade of ASC promotes the growth of melanoma tumors [ 314 ]. On the other hand, In some cases, the activation of the inflammasome can suppress antitumor immunity. For instance, when B16-F10 melanoma cells or RM-1 prostate cancer cells are delivered intravenously (as opposed to subcutaneously) into mice, the activation of NLRP3 is associated with increased lung metastasis. The harmful impact of NLRP3 in melanoma may stem from its inhibitory effect on the activation of NK cells, which are responsible for secreting IFNγ and killing tumor cells.In some cases, inflammasome activation can suppress antitumor immunity. For example, when B16-F10 melanoma or RM-1 prostate cancer cells are delivered intravenously into mice, NLRP3 activation is linked to increased lung metastasis. This detrimental effect may be due to NLRP3’s inhibition of NK cell activation, which is crucial for secreting IFNγ and killing tumor cells [ 310 ]. Recombinant IL-18 increases lung metastasis when injected into mice twice a week [ 311 ]. The knockdown of the gene encoding ASC suppresses the growth of melanoma xenograft tumors [ 314 ]. The types of cells, tissues, and organs involved in an inflammasome significantly influence its characteristics related to tumor promotion and suppression. The biological link between inflammasomes and cancer offers promising opportunities for exploring novel anticancer therapies.

Besides, other studies also point to the tumor-suppressive function of inflammasomes like NLRP3, NLRP1, NLRP6, and Pyrin in the initiation and spread of some malignancies, including colorectal cancer [ 315 ]. Recently, some inhibitors and agonists of these inflammasomes exhibit anti-tumor effects. For example, the small molecule OLT1177 suppressed tumor growth by inhibiting NLRP3 [ 316 ]. OLT1177 and another NLRP3 inhibitor MCC950 reduced tumor growth in melanoma [ 317 , 318 ]. Nigericin controls tumor growth by activating NLRP3 in breast cancer and neuroblastoma [ 319 ]. Since the multifaceted role of inflammasomes in carcinogenesis, clarifying the mechanism of action in different tumors will provide novel therapeutic approaches for cancer treatment and prevention. Here, we will summarize the promoting and suppressive effects of these inflammasomes and their inhibitors and agonists in cancer initiation and development. A comprehensive list of the role of these inflammasomes in cancer is also shown in Table 7 .

The role of NLRP1 in inflammation-mediated carcinogenesis

The receptor NLRP1, the adaptor protein ASC, and the effector protein caspase-1 make up the multi-protein complex known as the NLRP1 inflammasome. NLRP1 is the first identified and currently recognized predominant inflammasome sensor protein in human keratinocytes, NLRP1 has its unique domain, which contains an effector C-terminal caspase recruitment domain (CARD), PYD, a central NBD, an LRP and a function to find domain (FIIND). In the absence of external stimuli, the NBD binds to LRR, inhibiting self-oligomerization and bringing the protein into an inactive state. When cells are exposed to external stimuli, such as viruses, UVB rays, and ribotoxic stress reactions, they bind to the LRR domain, then induce a conformational change in NLRP1 and expose PYD and CARD domains. The downstream proteins which containing PYD and CARD are then mediated, such as the homologous interaction between ASC and caspase-1. Dipeptidyl protease (DPP), anthrax lethal toxin (LT), and parasites can activate NLRP1 [ 320 ].

Database analysis indicates that NLRP1 has a distinct expression pattern across various tumors, and patients with high NLRP1 expression generally have a better prognosis in lung adenocarcinoma (LUAD) and pancreatic adenocarcinoma (PAAD) [ 321 ]. The activation of the NLRP1 sensor protects against colitis-associated CRC through mechanisms dependent on effector cytokines [ 315 ]. NLRP1 is also positively correlated with an increased risk of prostate cancer [ 322 ]. The dysfunctions in the NLRP1 pathway are also linked to skin cancers, including melanoma, Kaposi sarcoma, and squamous cell carcinoma [ 323 ]. Increased expression of NLRP1 was significantly associated with immune cell infiltration in gastric cancer [ 324 ]. An endogenous thioredoxin (TRX) has been identified as a binder to NLRP1 and inhibits NLRP1 inflammasome activation. This opens opportunities for therapeutic intervention in NLRP1 inflammasome activation in the future.

The role of NLRP3 in inflammation-mediated carcinogenesis

The NLRP3 inflammasome is widely present in immune cells. As the most thoroughly studied inflammasome, NLRP3 inflammasome includes the sensor NLRP3, the adaptor ASC, and the effector caspase-1. NLRP3 consists of three domains, a central nucleotide-binding domain (NBD), a C-terminal leucine-rich repeat (LRR), and an N-terminal PYD. ROS production, ionic flux, mitochondrial dysfunction, and lysosomal damage are the four main activation mechanisms of NLRP3 inflammasome. Under the stimulation of microbial or endogenous molecules like TLR ligands, NF-κB is activated, and pro-IL-1β, pro-IL-18, and NLRP3 are induced. Then, various stimuli like extracellular ATP, glucose, bacterial and virus infection, mitochondrial damage/dysfunction, and more facilitated the maturation of pro-IL-1β and pro-IL-18, promoting the activation of NLRP3 inflammasome.

NLRP3 and NLRP3 inflammasome members like caspase-1, IL-1β and IL-18 are potential therapeutic targets due to their role in inflammation-associated diseases and cancer. Recent research reported that NLRP3 inflammasome-related genes were dysregulated in 15 cancers [ 325 ]. NLRP3 is overexpressed and activated in several cancers, like non-small cell lung cancer [ 326 ], melanoma [ 327 ], and more. Patients with cancer have a higher frequency of Nlrp3 polymorphism, such as pancreatic cancer [ 328 ], melanoma [ 329 ], and others. They were introduced as a double-edged sword in tumorigenesis. On one hand, the NLRP3 inflammasome promotes tumor formation and metastasis in breast cancer [ 330 ], and overexpressed human IL-1β in mice stomach increases the risk of gastric cancer [ 331 ]. NLRP3 affects the adaptive immune system to promote carcinogenesis in pancreatic cancer [ 332 ], and pharmacologic blocking of NLRP3 enhances the efficacy of immunotherapy [ 318 ]. NLRP3 signaling promotes T cell differentiation into tumor-promoting T cell populations and restricts antitumor T cell immunity [ 333 ]. NLRP3-mediated IL-1β production promotes pancreatic ductal adenocarcinoma by immunosuppression [ 334 ]. On the other hand, mice deficient in NLRP3 are hypersusceptible to carcinogen-induced colitis-associated cancer (CAC) [ 335 ]. While NLRP3 inhibition via mitophagy prevents CAC, indicating a harmful role of NLRP3 in CAC [ 336 ]. The differences in gut microbiota, genetic background, and experimental technique may explain the inconsistent effects of NLRP3 in CAC. Besides, NLRP3 is down-regulated in hepatic cancer tissues [ 337 ], and the up-regulation of NLRP3 inhibits hepatic cancer cell growth [ 338 ]. The varying functions of NLRP3 in the etiology of cancer present novel prospects and obstacles in comprehending its dual roles of pro- and anti-tumorigenic effects. The tumor microenvironment may have an impact on these many functions by altering NLRP3 activity. Furthermore, it appears that NLRP3 plays distinct roles in the pathophysiology of cancers that originate in particular organs due to its variable expression in different cells and tissues, and elucidating the role and mechanism of NLRP3 in different cancers will contribute to precision therapy.

The role of NLRC4 in inflammation-mediated carcinogenesis

NLRC4 contains three domains: the N-terminal CARD domain, the C-terminal LRR domain, and the NACHT domain. NACHT domain is composed of the NBD, helical domain 1 (HD1), winged helix domain (WHD), and helical domain 2 (HD2). A functional type IV secretion system (T4SS) for L. pneumophila or a functional type III secretion system (T3SS) for S. Typhimurium, S. flexneri, and P. aeruginosa is necessary for NLRC4 inflammasome activation [ 339 ]. Regulatory mechanisms also impact NLRC4 activation, mostly comprising transcription control and post-translation changes, specifically phosphorylation and perhaps ubiquitination. Interferon regulatory factor (IRF) 8 induces NLRC4 transcription, and infection with S. typhimurium induces NLRC4 phosphorylation at serine 533 [ 340 ]. Flagellin also induces NLRC4 phosphorylation but can’t activate NLRC4 inflammasome [ 341 ]. NLRC4 has been shown to express differently yet variably across various tumor tissues. For example, NLRC4 mRNA level is increased in stomach cancer, glioma, and breast cancer, but it is decreased in colorectal cancer compared with normal adjacent tissues [ 339 ]. However, NLRC4 mRNA is almost unchanged in hepatocellular carcinoma [ 342 ]. And there is no agreement regarding its role in any form of cancer development, even in the same tumor type. Knocking out NLRC4 promotes tumor formation in colon cancer [ 343 ] and melanoma [ 344 ]. Higher NLRC4 expression is closely related to poor prognosis in breast cancer [ 345 ] and glioma [ 346 ]. Activated NLRC4 inflammasome activates IL-1β, which promotes breast cancer progression by adipocyte-mediated vascular endothelial growth factor A (VEGFA) expression and angiogenesis [ 345 ]. Besides, in colitis-associated tumorigenesis, the role of NLRC4 depends on how NAIPs function. NAIPs have protective effects on colon cancer development, which is independent of NLRC4 [ 347 ]. Even though there isn’t a consensus on the involvement of NLRC4 or NAIP in cancer, the necessity to employ littermate controls in these experiments will improve future research consistency and reproducibility. Furthermore, the discovery of NAIPs’ or NLRC4’s inflammasome-independent activities in carcinogenesis is intriguing because it might reveal new route targets for the creation of immunotherapies.

The role of NLRP6 in inflammation-mediated carcinogenesis

As a recently identified receptor in the mammalian innate immune system, the NOD-like receptor family pyrin domain containing 6 (NLRP6) was formerly known as PYPAF5 [ 348 ]. It comprises N-terminal PYD, central NBD, and C-terminal LRR domain. Following the recognition of PAMP and DAMP, NLRP6 forms the NLRP6 inflammasome by assembling with ASC and Caspase-1. This process facilitates the maturation of pro-IL-1β and pro-IL-18, as well as gasdermin-D-induced pyroptosis. NLRP6 functions as an inflammasome or a non-inflammasome in a variety of ways. Various factors can regulate the activation of NLRP6. For example, mouse macrophages bind to lipoteichoic acid and stimulate the assembly of the NLRP6 inflammasome [ 349 ]; microbial signals of type I IFN and PPAR-γ agonists regulate NLRP6 transcription [ 350 , 351 ]; microbial metabolites activate or inhibit the NLRP6 inflammasome [ 352 ].

NLRP6 gene-deficient mice got more colitis-associated colorectal tumors after AOM/DSS treatment [ 313 ]. Elinav’s experiment suggests that the main source of active IL-18 generation through NLRP6 may be intestinal epithelial cells [ 353 ], which explains that NLRP6 gene-deficient animals’ serum and colon tissue showed decreasing levels of IL-18 with time but not IL-1. NLRP6 also plays a critical regulatory role in the linked pathogenic changes before HCC. For example, NLRP6 inflammasome and effector protein IL-18 suppress the development of NAFLD/nonalcoholic steatohepatitis (NASH) and metabolic syndrome by regulating intestinal microbiota [ 354 ]. NLRP6 overexpression reduces steatosis, inflammation, and fibrosis and lowers the production of CCL20 in alcoholic hepatitis (AH) animal models [ 355 ]. On the contrary, inhibiting the activation of NLRP6 inflammasome may improve liver steatosis in mice [ 356 ]. The contradictory conclusions regarding the role of NLRP6 in HCC may be due to the different stages of the disease and the differences in experimental models and methods. Further studies are needed to define the role of NLRP6 in the development and spread of HCC and comprehend the extent to which NLRP6 switches from inhibiting tumor growth to promoting malignancy. Besides, NLRP6 functions as a tumor suppressor factor in gastric cancer (GC) [ 357 ] while promoting small cell lung cancer (SCLC) metastasis [ 307 ]. Even though there is low or no expression of NLRP6 in other organs except for the colon, liver, and stomach, it’s also related to other organ diseases such as brain injury [ 358 ] and acute renal injury [ 359 ]. These suggest the potential role of NLRP6 in the carcinogenesis of these organs, and further studies are needed to expand the cognitive boundaries of NLRP6 research.

The role of AIM2 in inflammation-mediated carcinogenesis

As the best-characterized member of the AIM2-like receptors (ALRs), AIM2 contains the N-terminal PYD domain and one or two C-terminal HIN domains (hematopoietic, interferon-inducible, and nuclear localization). The multicomponent AIM2 inflammasome is formed when AIM2 recognizes dsDNA and recruits the adaptor protein ASC, which then activates caspase-1 [ 360 ]. AIM2 can be directly activated by transfection of dsDNA into the cytoplasm [ 361 ] and DNA derived from the gut microbiota or host-DNA released after intestinal injury [ 362 ]. While AIM2 activation is negatively regulated by several factors such as IFI16-β [ 363 ], IFN-inducible protein PYD-only protein 3 (POP3) [ 364 ], and the viral protein pUL83 released during human cytomegalovirus (HCMV) [ 365 ], herpes simplex virus-1 (HSV-1) tegument protein VP22 [ 366 ], hepatitis B e-antigen (HBeAg) [ 367 ], HCMV IE86 protein [ 368 ] and others. Besides, ubiquitinated TRIM11 promotes p62-dependent selective autophagy-induced AIM2 inflammasome degradation following DNA stimulation [ 369 ].

AIM2 has bidirectional roles in tumorigenesis in different types of cancer. In hepatic and colon cancer, AIM2 suppresses tumor growth [ 370 ], whereas in cutaneous squamous cell carcinoma, it promotes tumor growth [ 371 ]. AIM2 contains a site for microsatellite instability, which leads to gene mutations in CRC and inhibits its development [ 372 , 373 ]. Additionally, it was demonstrated that AIM2 has a role in the pathophysiology of DNA damage caused by chemotherapy, suggesting that medications targeting AIM2 may offer therapeutic advantages during radiation therapy [ 362 ]. These indicate that suppressing the activity of AIM2 inflammasome could be investigated due to their role in carcinogenesis. During the past decade, several synthetic inhibitors of AIM2 such as suppressive oligodeoxynucleotides [ 364 ], pyrin-containing proteins, and antimicrobial cathelicidin peptides [ 374 ] have been discovered, and exploring their anti-tumor effect and underlying mechanisms are promising strategies for cancer prevention and treatment.

The role of inflammasome adaptor ASC in inflammation-mediated carcinogenesis

In human leukemia cells treated with chemotherapeutics drugs, ASC was first identified as a protein that aggregates (or “specks”), which was also known as PYCARD/Target of Methylation-induced Silencing-1 (TMS1). The ASC/TMS1 protein has a 22 kDa structure and comprises two domains: the C-terminal CARD domain and PYD domain [ 375 ]. Several immune and normal epithelial cells express ASC/TMS1, which localizes in the nucleus, redistributes in the cytoplasm during activation, and finally aggregates into specks [ 376 ].

ASC can be either increased in tumor cells and overexpressed in the myeloid compartment (mostly TAMs) within the tumor microenvironment, or downregulated in malignancies, primarily due to aberrant methylation. On one hand, it is a key adapter molecule of the inflammasome complex, which is responsible for mediating the release of inflammatory cytokines of IL-1β and IL-18, which were known to have tumor-promoting effects [ 377 – 379 ]. Besides, ASC also exhibits pro-tumor effects through other indirect pathways such as chronic inflammation, macrophage recruitment, IL-17 pathway activation, angiogenesis, and others [ 378 ]. On the other hand, ASC was downregulated in several types of cancer, and the tumor-suppressive effect of ASC was supported by the discovery that methylation silences its expression and prevents tumor cells from passing through apoptosis [ 380 ]. Besides, the regulatory effect of ASC on thymic stromal lymphopoietin (TSLP) secretion by cancer-associated fibroblasts (CAFs) contributes to improving the overall survival of pancreatic cancer patients [ 381 ]. ASC delays UV-induced skin tumorigenesis [ 382 ]. ASC inhibits lung cancer suppression via Bcl-2 and pSrc [ 383 ]. Restoring ASC expression makes colorectal cancer cells more susceptible to caspase-independent cell death caused by genotoxic stress [ 380 ]. In addition, ASC showed dual roles even in the same type of tumor. For example, ASC inhibits tumorigenesis in primary melanoma, while ASC promotes tumorigenesis in metastatic melanoma [ 314 ]; mice had fewer tumors when ASC was specifically deficient in myeloid cells, while mice had more tumors when ASC was specifically deficient in keratinocyte cells [ 384 ]. These opposing functions of ASC may be due to the tissue or cell-specific expression context, and dissecting the role of ASC in different cancer types and additional research on ASC and its upstream and downstream mediators may improve our comprehensive of molecular processes behind carcinogenesis and contribute to the ASC targeting strategies for cancer treatment and prevention.

Targeting components of the extracellular matrix for cancer chemoprevention

As a highly dynamic structure, the extracellular matrix (ECM) is present in all tissues and constantly undergoing controlled remodeling. ECM comprises large, insoluble proteins mainly formed of separate structural domains with highly conserved sequences and arrangements. These domains are glycosylated and often have sulfated glycosaminoglycan chains, resulting in negative charges [ 385 ]. This characteristic of ECM molecules gives them great potential to interact with other charged molecules, like growth factors and chemokines, to affect the accessibility or local concentration of these factors [ 386 ]. Since collagen, the most abundant ECM component, was first identified and characterized in the 1930s.

In chronically inflamed tissues, the ECM fragments or ECM molecules are upregulated, and they’re modulated by proteases, especially MMPs, and inflammatory cytokines such as TNF, IFNγ, and TGFβ generated by extravasating cells or activated tissue-resident cells. Recent research has found that immune cells can be stimulated by ECM components or fragments that are increased during inflammation, thus sustaining the inflammatory response. On the one hand, ECM can serve a structural role as a barrier or scaffold for cells that invade inflamed tissues. On the other hand, the biophysical characteristics and their biochemical makeup provide immune cells with specific signals that regulate proliferation, migration, apoptosis, adhesion, differentiation, and survival.

Aberrant ECM influences immune cell behavior, such as infiltration and activation, and plays a role in cancer metastasis. For example, activating the collagen receptor DDR1 can enhance macrophage infiltration in atherosclerotic plaques [ 387 ]. The size and density of collagen fibrils can influence the migration of immune cells [ 388 ]. Although immune cell infiltration is promoted, collagen type I hinders macrophages from effectively killing cancer cells by blocking their polarization and subsequent activation [ 389 ]. This highlights the complex characteristics of how ECM deregulation modulates the immune response. Furthermore, breast cancer cells with high levels of the hyaluronan receptor CD44 have a better survival rate compared to those with low CD44 levels [ 390 ]. This indicates that hyaluronan and possibly other components of the extracellular matrix support the survival of metastatic cancer cells.

Tenascin-C (TNC) is a glycoprotein that plays a significant role in the ECM and is notably expressed in pathological conditions, particularly in cancer and chronic inflammatory diseases. TNC activates TLR4, which in turn stimulates macrophages and fibroblasts to release pro-inflammatory cytokines such as IL-6, IL-8, and TNF-α [ 391 ], and affects the recruitment of immune cells [ 392 ]. Higher TNC expression was observed in melanoma cells from advanced tumors and metastases, while early melanoma tumors and normal melanocytes displayed weak or absent TNC expression [ 393 ]. Tenascin-C is located in the bone endosteum and contributes to the development of prostate bone metastases [ 394 ]. TNC deficiency in human breast cancer cells significantly decreases metastasis to the lungs and bones in xenograft models [ 395 ].

Dysregulated ECM remodeling leads to many diseases, including cancer. As one of the major components of cancer, the ECM plays various crucial roles in signaling regulation, microenvironment modulation, and mechanical support. The ECM shows multifaceted effects in regulating multiple hallmarks, including angiogenesis, tumor progression, immune response, and cancer cell migration of cancer. Under specific circumstances, the ECM restrains malignant tumor progression [ 396 ]. However, the ECM also promotes tumor progression [ 389 ]. Collagen IV over-expression boosts cell survival of lung cancer [ 397 ]. The ECM also facilitates the metastasis of cancer cells [ 398 ]. The miR-29 over-expression inhibits metastasis by regulating gene expression in ECM remodeling in breast cancer [ 399 ]. This suggests that blocking the ECM molecules may be therapeutically beneficial for cancer prevention and treatment. The ECM components including tenascin C, endostatin, tumstatin, canstatin, arresten, and hexastatin also have pro- and anti-angiogenic functions. For example, tenascin C promotes cancer cell proliferation and induces angiogenesis [ 400 ]. Arresten suppresses the angiogenesis of HUVECs by blocking PI3K/Akt signaling pathway [ 401 ]. The ECM plays a vital role in regulating immune responses. For example, the ECM niche in the spleen promotes the differentiation and survival of marginal zone B cells to support antibody production [ 402 ]. Besides, matrikines regulate immune cell behaviors such as the interaction of immune cells with cancer cells [ 403 ], the recruitment and activation of immune cells [ 404 ], and more. Here, we will summarize the role of the ECM components including ECM proteins, ECM fragments, the proteases that cleave the ECM, the MMPs that degrade the ECM, and others, the underlying mechanisms are also illustrated. A deeper comprehension of the biological activities of the ECM will provide intriguing opportunities for therapeutic intervention of cancer. More details regarding the function of ECM proteins and fragments in cancer are provided in Table 8 .

The chemo-preventive effects of FDA-approved anti-inflammatory drugs in cancer chemoprevention

Long-term users of aspirin or other NSAIDs had a decreased incidence of cancer, which offers encouraging opportunities for cancer chemoprevention. Aspirin can reduce the risk of tumor occurrence [ 405 ], prevent colorectal cancer [ 406 ], inhibit metastasis of melanoma and breast cancer [ 407 ], and more. Besides, steroidal anti-inflammatory drugs such as dexamethasone, suppress tumor growth of non-small cell lung cancer [ 408 ], enhance gynecologic cancer chemotherapy [ 409 ], and more. These FDA-approved anti-inflammation drugs have well-established safety profiles, making them potentially valuable tools for cancer chemoprevention. Clarifying the anti-tumor effects and underlying mechanisms of the anti-inflammation drugs will provide novel options and targets for cancer prevention and treatment. Here, we will summarize the effects and underlying mechanisms of FDA-approved anti-inflammatory drugs, and the advantages and disadvantages of these drugs’ application in cancer chemoprevention will be also be discussed.

The anti-tumor effect of non-steroidal anti-inflammatory drugs

The chemo-preventive effect of NSAIDs in cancer was proposed in 2002 [ 410 ]. Epidemiological studies have shown a consistent 40–50% reduction in the risk of developing CRC by taking NSAIDs [ 411 ]. The epidemiological evidence supporting the efficacy of aspirin for the prevention of CRC is substantial [ 412 ]. As a classic NSAID, the role of aspirin in cancer chemoprevention has been well-studied. For example, aspirin reduces the risk of breast cancer [ 413 ] and pancreatic cancer [ 414 ], reduces mortality in endometrial cancer patients [ 18 ] and colon cancer [ 415 ], inhibits tumor progression of HCC [ 22 ], and pancreatic cancer [ 416 ] and others. Except for aspirin, other NSAIDs like indomethacin, acetaminophen, ibuprofen, meloxicam, and others also exhibit anti-tumor effects in various cancers. For example, indomethacin inhibits cell proliferation and invasion in colorectal cancer [ 417 ] and breast cancer [ 418 ], induces apoptosis of colon cancer [ 419 ], and suppresses angiogenesis of colon cancer [ 420 ] and others. A comprehensive list of the anti-tumor properties of NSAIDs is shown in Table 9 .

The anti-tumor effect of steroidal anti-inflammatory drugs

Unlike NSAIDs, the anti-tumor effect of steroidal anti-inflammatory drugs is controversial. As a commonly used class of steroid anti-inflammatory drugs, on the one side, glucocorticoids (GCs) such as dexamethasone as an adjunctive treatment strategy for lymphoma in the clinic, they can reduce tumor size and improve patient’s tolerance to chemotherapy [ 421 ]. About other solid tumors, GCs reduce treatment-related toxicity after surgery or radiotherapy in brain tumors [ 422 ] and reduce the risk of lung cancer [ 423 ]. On the other side, GCs favor pancreatic cancer progression [ 424 ], promote metastasis of breast cancer [ 425 ], induce resistance in prostate cancer [ 426 ], and others. A comprehensive list of the anti-tumor properties of steroidal anti-inflammatory drugs is shown in Table 10 .

The outcome of clinical application of anti-inflammation drugs in cancer chemoprevention

Although cytokines are important regulators of both innate and adaptive anticancer immunity, their extreme toxicity, pleiotropy, and poor drug-like qualities make them challenging to utilize as treatments [ 427 , 428 ]. Developments in immune checkpoint blocking, protein engineering, and receptor biology and biochemistry drive rekindled interest in developing cytokine therapies [ 429 , 430 ]. Clinical prospects have emerged from engineering strategies targeted at disentangling cytokines’ pro- and anti-tumorigenic characteristics, which have shown encouraging preclinical outcomes [ 431 ]. Cytokines are the first effective cancer immunotherapy to provide humans with long-lasting anti-tumor immunity. Recombinant interferon (IFNα2b) and IL-2 are approved cytokine therapeutics for cancer clinical treatment [ 432 ].

Other cytokines such as IL-4, IL-6, IL-7, IL-9, IL-10, IL-12, IL-15, IL-18, IL-21, IL-2R, IL-4R, IL-5R, IFNα, IFNβ, IFNγ, TNFα and more have also been applied in clinical trials. For example, in a phase I/II study ( NCT00000769 ), IL-4 at the dose of 1.5 microg/kg/day is poorly tolerated in patients with advanced AIDS-related Kaposi’s sarcoma (KS) and didn’t show an effective role in KS [ 433 ]. The anti-tumor effect of IL-4 in patients is ambiguous, and more clinical trials are recruiting or undergoing in other cancers such as recurrent malignant astrocytoma ( NCT00003842 ) and ER + breast cancer ( NCT05967884 ). In phase II clinical trial ( NCT00433446 ), a monoclonal antibody against IL-6 (CNTO328, also called siltuximab) was applied to pretreated patients with castration-resistant prostate cancer, CNTO328 resulted in a prostate-specific antigen (PSA) response rate of 3.8% and a response evaluation criteria in solid tumors (RECIST) stable disease rate of 23% [ 434 ]. In a phase 2 randomized study ( NCT00911859 ), CNTO328 at 8.3 and 11 mg/kg doses were well tolerated, while CNTO328 didn’t significantly improve the complete response (CR) and long-term outcomes in patients of multiple myeloma [ 435 ].

Besides, several clinical trials have examined the combination of anti-inflammatory agents and ICIs. For instance, a phase 2 trial study ( NCT03631407 ) investigated the combination of vicriviroc (a CCL5 antagonist) administered at doses of 150 or 250 mg alongside pembrolizumab at 200 mg. This combination demonstrated limited antitumor activity in patients with advanced or metastatic microsatellite stable (MSS) or mismatch repair-deficient (dMMR) CRC. However, the toxicity associated with this combination treatment was manageable [ 436 ]. In another phase 2 trial study ( NCT03396952 ), the efficacy of high-dose aspirin in combination with ICIs is similar to that of ICI alone [ 437 ]. In a phase Ib/II trial study ( NCT02807844 ), the combination of lacnotuzumab (CSF-1 inhibitor) and spartalizumab (PD-1 inhibitor) did not meet the gating criteria for efficacy [ 438 ]. Numerous clinical trials are currently recruiting participants or ongoing. For instance, siltuximab, an IL-6 inhibitor, is being tested to prevent severe irAEs during the rechallenge of ICIs in patients with advanced cancer ( NCT06470971 ). Additionally, drugs used in chemokine modulation therapy, such as celecoxib, recombinant interferon alfa-2b, and rintatolimod, have been combined with pembrolizumab in the treatment of metastatic triple-negative breast cancer ( NCT03599453 ). Further investigation is needed to fully evaluate the clinical utility and identify the patient subgroups that are most likely to benefit from the combination of anti-inflammatory agents with ICIs. More information about the clinical trials of these cytokines or their antibody or their derivatives is summarized in Table 11 .

The application of artificial intelligence (AI) in inflammation-related cancer for cancer chemoprevention

In recent years, AI has gained significant popularity. With the advancement of deep learning and the availability of extensive imaging databases, AI-based computer-aided diagnostic (CAD) systems—which incorporate machine learning (ML), deep learning (DL), and artificial neural networks (ANN)—are increasingly being used to standardize and improve the evaluation of medical imaging.

AI models have been used to identify inflammatory and immune cells in cancer tissues. For instance, deep learning techniques have been employed to detect tumor-infiltrating lymphocytes (TILs), which could serve as a potential prognostic marker for testicular germ cell tumors [ 439 ]. Deep convolutional neural networks based on supervised learning have been used to quantify the biomarkers of immune cells in the lung cancer microenvironment [ 440 ]. TILs densities and spatial structures can be analyzed using deep learning on pathology images, providing insights into the tumor-immune microenvironment [ 441 ]. Deep learning supervised by antibodies was utilized to quantify tumor-infiltrating immune cells, an emerging prognostic biomarker in breast cancer samples [ 442 ]. AI-based pathology served as a biomarker for progression-free survival in patients treated with atezolizumab and bevacizumab for hepatocellular carcinoma [ 443 ]. Identifying PLA2G1B, a gene crucial for lipid metabolism and inflammation, suggests it may serve as a preventive marker for lung cancer through bioinformatics and machine learning methods [ 444 ].

Artificial intelligence has recently emerged as a powerful and promising tool for developing anti-tumor medications more quickly, affordably, and effectively [ 445 ]. Due to the crucial role of TLR4 in pro-inflammatory responses, and considering the costly, time-consuming, and labor-intensive nature of traditional drug design approaches, novel TLR4 modulators identified through artificial intelligence and computer-assisted drug design show great promise and have demonstrated positive results [ 446 ]. Due to their high selectivity and low toxicity, anti-inflammatory peptides (AIPs) have shown greater therapeutic potential against inflammatory diseases compared to small compounds. Additionally, machine learning plays a crucial role in predicting peptides [ 447 ].

Artificial intelligence solutions for endoscopy-based cancer evaluation hold great promise for the future. However, the application of these models in clinical practice faces several challenges, including the need for more robust validation studies and overcoming regulatory hurdles. At the same time, AI facilitates data-driven decision-making, helping to expedite drug discovery and development while reducing failure rates. Additionally, AI-powered precision medicine allows doctors to tailor early therapies to the individual needs of each patient.

Open questions/Future perspective

It is now evident that inflammatory cells and related inflammatory pathways significantly influence tumor growth. However, several issues still need to be addressed. 1) In the absence of an external carcinogenic agent, can inflammation itself lead to neoplasia? While various studies have suggested that inflammation can cause cancer without the presence of exogenous carcinogens, evidence shows that more DNA mutations were observed in a mouse model of bowel inflammation lacking IL-10 when exposed to external carcinogens [ 448 ], and more powerful proof is required to make such a disclosure. 2) Due to the dual role of inflammatory molecules, such as inflammasomes and interleukins, in cancer development and progression, it is important to consider the question about whether we can suppress tumor growth by shifting the balance between “bad” inflammation and “good” inflammation? The adaptive, humoral, and innate immune systems all play integral roles in the complex relationship between local and systemic inflammation and tumor growth. Therefore, triggering an effective anti-tumor adaptive immune response is crucial and requires careful attention. Recently, the use of bromodomain and extra-terminal domain (BET) protein inhibitors (iBET) has been reported to induce cell death and reduce the aggressiveness of oral squamous cell carcinoma (OSCC) [ 449 ]. iBET protects mice from pancreatic inflammation caused by LPS and the resulting cytokine storm, while also inhibiting cell proliferation in pancreatic cancer [ 450 ]. Another promising approach is to restore a balanced host response by normalizing the inflammatory network. This involves reducing high levels of pro-inflammatory cytokines and other tumor-promoting characteristics of infiltrating cells while increasing the levels of anti-inflammatory cytokines. 3) Do sex steroid hormones play a role in the interplay between inflammation and cancer? The occurrence of tumors varies between genders due to differing sex hormones. Analyzing the interaction between these hormones and inflammation in cancer development could enhance the treatment of hormone-related cancers, such as breast, lung, ovarian, cervical, and prostate cancers. Recent studies have shown that Treg cells, which play a crucial role in managing immune responses and reducing tissue inflammation, are more abundant in male visceral adipose tissue (VAT) compared to females. These differences in Treg cell populations are influenced by the tissue environment and shaped by sex hormones, which help to decrease inflammation in adipose tissue [ 451 ]. Considering the widespread use of selective androgen receptor modulators and selective estrogen receptor modulators like tamoxifen, understanding the interaction between sex hormones, inflammation, and cancer will significantly influence the clinical treatment of cancer.

Discussion

Cancer is still the second leading cause of death after cardiovascular disease in the world, the main reason is that about 50% of cancers are diagnosed at a late stage. The limited efficacy of existing treatment methods and the high failure rate in drug development make the situation more complex, and there is an urgent need for a better understanding of disease mechanisms, the development of early detection technology, and cancer chemoprevention strategies. Here, we systematically analyzed the role of inflammation and its related molecules in tumors. We expect that a substantial amount of information and intricacies continually uncovered in the area will eventually be condensed into a few key principles that regulate the molecular and cellular processes underpinning inflammation that promote tumor growth.

The role of inflammatory molecules in cancer has attracted the researchers’ attention during the past decades. New insights into the pro- or anti-tumor effect in the tumor and its microenvironment have given impetus to drug discovery and patient evaluation of inflammation-directed strategies. For example, as the most effective and widely distributed family of cytokines, IFN-Is, or type I interferons, are essential for launching a successful anti-tumor response. Antigen-presenting cells require interferon-alpha to trigger T cell responses; additionally, IFN-Is directly boost CD8 + T cell activity and cytotoxicity, stimulate CD4 + Th1 cell development, augment cytotoxicity from natural killer cells, and limit regulatory T cells. However, IFN-Is induce the expression of negative regulatory molecules, which can reduce immunological responses and induce fatigue, thus facilitating the growth of tumors. Besides, other inflammatory molecules such as interleukins, tumor necrosis factors, colony-stimulating factors, chemokines, and inflammasomes also showed multifaceted effects in cancer. The two-side effect may depend on the cancer type, time, cells present, total IFN-I signal levels, and others. Therefore, further studies are needed to dissect the dual role of these inflammatory molecules in different cancer models, which will enable the identification of novel molecular and immunological targets and lead to the development of novel therapeutic strategies. Recently, researchers created a portable smart blue-light controlled (PSLC) gadget based on optogenetic technology. The findings demonstrate that blue light can efficiently control pro-inflammatory cytokine expression in both in vitro and in vivo settings, which offers a unique strategy for cytokine therapy [ 452 ].

FDA-approved non-anticancer drugs- “old medicine”, have obvious advantages in anti-tumor treatment—“new use”, because FDA-approved drug applications could better avoid numerous obstacles and uncertainties in every step of converting drugs into clinical applications. This suggests that the application of non-anticancer drugs may be a promising strategy for cancer chemoprevention. The evident role of inflammation in cancer development and progression prompted the application of anti-inflammatory medications as a therapeutic strategy. While the application of anti-inflammatory drugs in clinical antitumor therapy still needs to overcome several obstacles. 1) Targeted delivery to the cancerous cell. Although the anti-inflammatory medications now approved by the FDA are undoubtedly effective, their off-target effects and toxicities make them less desirable options for cancer therapy when taken at the current dosages and frequency. Rather, to improve drug targetability and reduce off-target adverse effects, recent developments in nanotechnology have facilitated a paradigm shift away from traditional anti-inflammatory medications and toward anti-inflammatory nano-therapeutics in cancer therapy. However, the field of anti-inflammatory nanomedicines is still in its infancy with little commercial application, and there is a great need to consider and identify the issues with nano-inflammatory therapies to aid in the practical clinical translation of commercially available anti-inflammatory nanotherapeutics. 2) Tumor cells have different or even opposite responses to these anti-inflammatory drugs. Abundant evidence indicates that anti-inflammation drugs are promising candidates for preventing carcinogenesis and cancer recurrence because of their availability and relatively low occurrence of side effects compared to other chemotherapeutic drugs. Nevertheless, due to the paucity of information and the complexity of carcinogenesis, these anti-inflammation drugs showed different or even inverse effects. Well-designed, long-term clinical trials are required to ascertain the clinical application potential of these medications, and additional trials are required to investigate the doses, kinds, and length of response of these drugs. 3) The side effects after long-term use. Although the FDA-approved anti-inflammatory drugs have far fewer side effects than chemotherapeutics, some anti-inflammatory drugs, such as aspirin, also showed obvious side effects after long-term use. The main side effects of NSAIDs are cardiovascular (CV) and renal adverse effects. While the main side effects of seroidal anti-inflammatory drugs such as glucocorticoids (GRs) are diabetes, glaucoma, and suppression of the hypothalamic–pituitary–adrenal axis, among others. NSAIDs cause cell death by directly targeting mitochondria, while NSAIDs have been shown to enhance mitochondrial health in dose-dependent ways [ 453 ], which suggesting that future research should focus on comparing equipotent dosages of these drugs. Additionally, it’s important to assess the alleviation of symptoms. There are ongoing efforts to develop selective GR agonists (SEGRAs) with the hypothesis that they are safer than traditional glucocorticoids. To support this hypothesis, appropriate in vitro and in vivo studies are needed to provide reliable experimental results. 4) Patients continue to experience other thromboembolic events despite aspirin therapy, which is known as aspirin resistance (AR). Besides, anti-inflammatory drugs may lead to a degree of drug resistance. For example, dexamethasone can increase the resistance of human tumor cells to ionizing radiation and chemotherapy [ 454 ].

Hence, larger-scale adoption of the chemoprevention strategy is likely to require improved identification of individuals for whom the protective benefits outweigh the harms. Such a precision medicine approach may emerge through further clarification of these anti-inflammatory drugs’ mechanism of action.

Acknowledgements

We would like to acknowledge the assistance of FigDraw in the creating cartoon illustrations.

Abbreviations

Interleukin

Tumor necrosis factor alpha

Nuclear factor-κB

Signal transducer and activator of transcription 3

Nonsteroidal anti-inflammatory drugs

Colorectal cancer

US Preventive Services Task Force

Death receptor 5

Food and Drug Administration

Toll-like receptors

Programmed cell death protein 1

Programmed cell death ligand 1

LC3-associated phagocytosis

LC3-associated endocytosis

Beta-amyloid

Interferon

Reactive oxygen species

IκB kinase

Immunity-related GTPase M

Absent in melanoma 2

FUN14 domain-containing 1

Matrix metalloproteinases

Cyclooxygenase

Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform

Protein kinase B

Phosphatase and tensin homolog

Wingless-type MMTV integration site family

Interleukin-4 fusion protein

African American

European American

Crown-like structures

T regulatory cells

Natural killer cells

Checkpoint inhibitors

Immune-related adverse events

High microsatellite instability

Peroxisome proliferator-activated receptor alpha

Metabolic syndrome

Methyladenine

Toll-like receptor

Nucleotide-binding domain leucine-rich repeat (NLR) and pyrin domain-containing receptor

Transforming growth factor beta

Endothelial cells

Vascular endothelial growth factor

Brain-derived neurotrophic factor

Tropomyosin receptor kinase B

C-X-C chemokine receptor

(C-X-C motif) ligand

CX3Chemokine receptor 1

CC-chemokine receptor 1

Epithelial-mesenchymal transition

DNA damage response

Interferon gamma

Signal transducer and activator of transcription 6

Epigallocatechin-3-gallate

Immune checkpoint blockade

Crohn’s disease

Ulcerative colitis

Inflammatory bowel disease

Rheumatoid arthritis

Nonmelanoma skin cancer

Human papillomavirus

Helicobacter pylori

Hepatitis B virus

Hepatitis C virus

Nonalcoholic fatty liver disease

Myelocytomatosis oncogene

Rats arcomaviral oncogene homolog

Kristen rats arcomaviral oncogene homolog

Non-small cell lung cancer

Von Hippel-Lindau

Janus kinase

IFN-stimulated gene (ISG) factor 3

Retinoic acid-inducible gene I

Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP)

Cyclic GMP-AMP synthase

Stimulator of interferon genes

Indoleamine-2,3-dioxygenase

Granulocyte/macrophage colony-stimulating factor

Macrophage colony-stimulating factor

Granulocyte colony-stimulating factor

Gai-protein-coupled seven-transmembrane-spanning receptor

Tumor microenvironment

Leucine rich repeat

Pyrin domain

Pyrin domain (PYD) domain-containing protein 1

NLR family caspase activation and recruitment domain-containing protein 4

NOD-like receptor family pyrin domain containing 6

Apoptosis-associated speck-like protein containing caspase activation and recruitment domain

Dextran sulfate sodium

Azoxymethane

C-terminal caspase recruitment domain

Function to find domain

Dipeptidyl protease

Lethal toxin

Lung adenocarcinoma

Pancreatic adenocarcinoma

Thioredoxin

Nucleotide-binding domain

Helical domain 1

Winged helix domain (WHD)

Helical domain 2

Type IV secretion system

Type III secretion system

Interferon regulatory factor

Nonalcoholic steatohepatitis

Alcoholic hepatitis

Gastric cancer

Small cell lung cancer

AIM2-like receptors

PYD-only protein 3

Human cytomegalovirus

Herpes simplex virus-1

Hepatitis B e-antigen

Target of methylation-induced silencing-1

Thymic stromal lymphopoietin

Cancer-associated fibroblasts

Extracellular metrix

Tenascin-C

Prostate-specific antigen

Response evaluation criteria in solid tumors

Complete response

Metastatic microsatellite stable

Mismatch repair-deficient

Artificial intelligence

Computer-aided diagnostic

Machine learning

Deep learning

Artificial neural networks

Tumor-infiltrating lymphocytes

Anti-inflammatory peptides

Bromodomain and extra-terminal domain

Bromodomain and extra-terminal domain (BET) protein inhibitors

Oral squamous cell carcinoma

Visceral adipose tissue

Portable smart blue-light controlled

Cardiovascular

Glucocorticoids

Selective GR agonists

Aspirin resistance

Authors’ contributions

All authors have contributed to the article and approved its publication. Y.X., F.L., designed and wrote the manuscript. Y.W. and Y.Z., prepared the figures. Y.J. and Q.W., modified the language. Z.D. and K.L., reviewed and edited the manuscript.

Funding

This work was supported by the National Natural Science Foundations of China (grant numbers: 82472998, 82303891, 82203594, 82473228, and 82303119, K. Liu, Y. Xie, F. Liu, Y. Jiang and Q. Wu), the Science and Technology Project of Henan Province (grant number: 232102310195 and 242102311082, Y. Xie and Y. Jiang), Henan Province Medical Science and Technology Joint Construction Project (grant numbers: LHGJ20210438, Y. Xie), the Postdoctoral Fellowship Program of CPSF (grant number: GZB20230669, F. Liu), the China Postdoctoral Science Foundation (grant number: 2023M743179 and 2024M763001, F. Liu and Qiong Wu), the China Postdoctoral Science Foundation, No.17 Special Funding (grant number: 2024T170828, F. Liu), the Fundamental Research Project of key scientific research in Henan Province (grant number: 23ZX007, Y. Jiang), and Key Research Project Plan for Higher Education Institutions in Henan Province (grant number: 24A310025, Q. Wu).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher's Note

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

Yifei Xie and Fangfang Liu contributed equally to this work.

Contributor Information

Zigang Dong, Email: dongzg@zzu.edu.cn.

Kangdong Liu, Email: kdliu@zzu.edu.cn.

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Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.