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He, Y.;  Huang, J.;  Li, Q.;  Xia, W.;  Zhang, C.;  Liu, Z.;  Xiao, J.;  Yi, Z.;  Deng, H.;  Xiao, Z.; et al. Gut Microbiota and Tumor Immune Escape. Encyclopedia. Available online: https://encyclopedia.pub/entry/36352 (accessed on 19 June 2025).
He Y,  Huang J,  Li Q,  Xia W,  Zhang C,  Liu Z, et al. Gut Microbiota and Tumor Immune Escape. Encyclopedia. Available at: https://encyclopedia.pub/entry/36352. Accessed June 19, 2025.
He, Yunbo, Jinliang Huang, Qiaorong Li, Weiping Xia, Chunyu Zhang, Zhi Liu, Jiatong Xiao, Zhenglin Yi, Hao Deng, Zicheng Xiao, et al. "Gut Microbiota and Tumor Immune Escape" Encyclopedia, https://encyclopedia.pub/entry/36352 (accessed June 19, 2025).
He, Y.,  Huang, J.,  Li, Q.,  Xia, W.,  Zhang, C.,  Liu, Z.,  Xiao, J.,  Yi, Z.,  Deng, H.,  Xiao, Z.,  Hu, J.,  Li, H.,  Zu, X.,  Quan, C., & Chen, J. (2022, November 24). Gut Microbiota and Tumor Immune Escape. In Encyclopedia. https://encyclopedia.pub/entry/36352
He, Yunbo, et al. "Gut Microbiota and Tumor Immune Escape." Encyclopedia. Web. 24 November, 2022.
Gut Microbiota and Tumor Immune Escape
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This entry is adapted from the peer-reviewed paper 10.3390/cancers14215317

The gut microbiota is a large symbiotic community of anaerobic and facultative aerobic bacteria inhabiting the human intestinal tract, and its activities significantly affect human health. Increasing evidence has suggested that the gut microbiome plays an important role in tumor-related immune regulation. In the tumor microenvironment (TME), the gut microbiome and its metabolites affect the differentiation and function of immune cells regulating the immune evasion of tumors. The gut microbiome can indirectly influence individual responses to various classical tumor immunotherapies, including immune checkpoint inhibitor therapy and adoptive immunotherapy. Microbial regulation through antibiotics, prebiotics, and fecal microbiota transplantation (FMT) optimize the composition of the gut microbiome, improving the efficacy of immunotherapy and bringing a new perspective and hope for tumor treatment. 

gut microbiota tumor microenvironment tumor immunotherapy immune checkpoint inhibitor

1. Introduction

The gut microbiota comprises numerous anaerobic and facultative aerobic bacteria living in the human gastrointestinal tract [1]. A stable gut microbiota is indispensable for maintaining the normal physiological function of the human body, directly or indirectly involved in the body’s digestion, metabolism, immunity, and inflammation, etc. [2]. Abnormal changes in gut microbiota have been shown to induce or promote a variety of diseases and pathological conditions, including cancer [3][4][5][6]. With the in-depth study of the microbiota, researchers have proposed several ways through which gut microbiota affects distant organs, such as the Microbiota–Gut–Brain Axis [7], the Microbiota–Gut–Bone Axis [8], and the Microbiota–Gut–Liver Axis [9]. These findings have enriched our understanding of the mechanisms by which gut microbiota affects disease states. The important role of gut microbiota in the initiation and progression of cancer has also been gradually discovered. The gut microbiota and its metabolites were found to promote the occurrence and development of colon cancer and hepatocellular carcinoma (HCC) [10][11], and the gut microbiota may increase the risk of a poor prognosis for breast cancer patients by affecting estrogen metabolism [12].
The imbalance of gut microbiota is mainly the decrease of good bacteria and the increase of bad bacteria. Therefore, to change this dysregulation, increase the proportion of anti-tumor beneficial bacteria and restore the intestinal beneficial bacteria ecology, such as prebiotics and FMT [13][14], can fight against the occurrence and development of tumors. Diet therapy is also a highly concerned treatment. High cholesterol diet can induce dysbiosis of the microbiota, leading to the progression of hepatocellular carcinoma (HCC). Reducing dietary cholesterol intake in HCC patients may be beneficial to the treatment of HCC [15]. High dietary fiber diet is also beneficial to the gut microbiota ecology of cancer patients. Dietary fiber supplementation can improve the dysregulation of intestinal flora and improve the effect of tumor immunotherapy [16].
With the development of immune surveillance theory, tumor immune escape has been recognized as an indispensable mechanism of tumorigenesis [17][18]. Tumor immune escape refers to the process in which tumor cells evade the surveillance of the immune system, avoiding the clearance. Tumor immune escape is achieved through the interaction between three factors: the tumor microenvironment (TME), the tumor cells, and the immune status of the body [19][20][21]. Gut microbiota is closely related to the human immune system. It can affect tumor immune escape by its own structure and metabolites, which is an important reason for tumor progression and poor prognosis [22][23].
The goal of tumor immunotherapy is to restore antitumor immunity to control and eliminate tumors. Tumor immunotherapy includes cytokine therapy, adoptive immune cell therapy, and immune checkpoint inhibitor therapy, etc. [24]. Since gut microbiota affects the efficacy of tumor immunotherapy by influencing the function of immune cells and the release of cytokines and chemokines, microbiota regulatory strategies, such as fecal microbiota transplantation (FMT), antibiotic cocktails, and prebiotics, are potential adjuvants to tumor immunotherapy [25][26][27].

2. Gut Microbiota Influences Tumor Immune Escape through Tumor Microenvironment

The tumor microenvironment (TME) contains components that inhibit/promote the proliferation and invasion of tumor cells [28]. Treg cells, TAMs (tumor-associated macrophages), MDSCs (myeloid-derived suppressor cells), immunosuppressive molecules, and immunoregulatory enzymes promote tumor growth, proliferation, and metastasis, while immune effector cells and immune effector molecules inhibit them. In the TME, the immunosuppressive network composed of immunosuppressive cells and their secreted immunosuppressive molecules is the most important reason for tumor immune escape and resistance to antitumor therapy [29]. Gut microbiota can influence the status of key components in the TME, affecting tumor immune escape.
Inflammation plays an important role in tumor immune evasion triggered by gut microbiota. As early as 1863, Virchow et al. observed that malignancy tends to occur at sites of chronic inflammation [30], suggesting a correlation between inflammation and tumorigenesis. Subsequently, epidemiological data strongly suggested that chronic inflammation is associated with an increased risk of cancer [31][32]. At the same time, there is inflammation in TME, where infiltrating cells such as macrophages, neutrophils, monocytes, and mast cells together with the secretion of cytokines and the interaction with the tumor constitute the complex inflammation of the TME and are the foundation of tumor immune escape. Recent studies have reported that gut microbiota can invade colonic epithelial cells and activate the intracellular signaling system to trigger the host inflammatory response [33][34]. These inflammatory reactions are closely related to the occurrence of gastrointestinal tumors [35][36].
Particular attention should be paid to the fact that angiogenesis is a common feature of the inflammatory response and tumor progression. The inflammatory microenvironment promotes tumor development by accelerating angiogenesis and disrupting adaptive immune response [37][38]. It has long been noted that colonizing gut microbiota can induce intestinal angiogenesis in germ-free mice [39]. Later studies demonstrated that this angiogenesis is mediated through the tissue factor (TF) [40], a membrane receptor that initiates an exogenous coagulation pathway and can promote tumor angiogenesis [41][42]. Gut microbiota closely links inflammation to tumor progression by promoting angiogenesis. Metabolites of gut microbiota promote specific angiogenesis in a NOD-like receptor-dependent manner and are associated with chronic intestinal inflammation [43]. Mucosal Escherichia coli expressing the AFA-1 operon upregulates the expression of HIF-1α in the intestinal epithelial cells, promotes angiogenesis, and induces inflammation, leading to tumor progression [44][45][46].
Because of the temporal and spatial proximity, colorectal cancer (CRC) is currently considered to be the cancer most affected by gut microbiota that is closely related to biological dysregulation, extensive changes in gut microbiota, and enrichment of certain microbial strains [47][48]. Gut microbiota plays a role in maintaining the homeostasis of the normal intestinal environment. However, once the intestinal environment is changed under the induction of internal or external factors or the composition of gut microbiota is unbalanced, gut microbiota may aggravate the inflammatory reaction and release inflammatory factors. These inflammatory factors influence the TME, promoting the occurrence and development of CRC [49]. In addition, the microbiota located in the gut can also affect tumors outside the gut through the maturation and migration of the body’s own immune system, such as in leukemia [50][51][52] and lymphoma [53][54][55].

3. Gut Microbiota and Tumor Immunotherapy

The proliferation of tumor cells is the result of the tumor evading the surveillance of the host immune system through a variety of mechanisms, such as the induction of immunosuppression in the TME and the downregulation of the expression of target antigens [56]. In recent years, the enhanced understanding of the tumor immune escape mechanism has led to the rapid development of tumor immunotherapy [57]. Tumor immunotherapy can help the body rebuild or strengthen antitumor immunity through various ways to cure or delay the tumor process [58][59]. Tumor immunotherapy includes chimeric antigen receptor (CAR)-T-cell therapy, immune checkpoint inhibitors (ICIs), CpG oligonucleotides, etc. Gut microbiota has been found to influence the response to immunotherapy and the occurrence of complications by modulating the infiltration degree of immune cells and the secretion of inflammatory factors in the TME [60][61][62]. 

3.1. Gut Microbiota Affects the Efficacy of Immune Checkpoint Inhibitors

ICIs target the regulatory pathways of T cells and re-expose tumor cells that have escaped immune surveillance to enhance antitumor immune responses [63]. Antibodies that block cytotoxic T lymphocyte-associated protein 4 (CTLA-4) or programmed cell death 1 (PD-1) pathways are the most commonly used ICIs [64][65]. ICIs have been shown to have good efficacy in melanoma, nonsmall cell lung cancer, and other tumors, but the interpatient variability of the treatment effect is still a concern [66].
In an ICI treatment targeting the PD-1/PD-L1 axis in melanoma patients, Response Evaluation Criteria in Solid Tumors (RECIST) were used to distinguish melanoma patients with or without a clinical response to ICI treatment, and they were labeled as responders or nonresponders. There was a significant difference in fecal microbial composition between responders and nonresponders. When fecal microbiota from responders and nonresponders were transplanted into melanoma mice that received PD-1 blockade treatment, the response was significantly enhanced in mice that underwent responder feces, while the response was not observed in mice that underwent nonresponders [67]. This suggests that the gut microbiota includes both favorable and unfavorable microbiota, and the composition of gut microbiota plays a role in regulating the therapeutic effect. Analysis of the TME revealed that this effect was due to enhanced activation of tumor antigen-specific CD8 T cells [68][69]. Higher concentrations of CD8 T cells were clustered in the TME of mice receiving fecal microbial transplantation from “responders”, and the infiltration degree of CD8 T bacteria was positively correlated with Faecalibacterium [70]. Bifidobacterium can directly induce DC maturation and cytokine synthesis and increase the number of CD8 T cells in peripheral areas and in the TME [71]. In addition to CD8 T cells, favorable flora can also increase the number and function of CD4 T cells in the body. An abundance of Faecalibacterium cells can improve the number of circulating CD4 T cells and promote cytokine response [70]. In view of the effects of gut microbiota on T cells, artificial regulation of microbiota composition is an effective strategy to assist ICI. Oral administration of Akkermansia muciniphila could induce the secretion of IL-12 from DCs and increase the accumulation of CCR9CXCR3CD4 T lymphocytes in mouse tumors, thus recovering the efficacy of the PD-1 blockade [72]. The mechanism of gut microbiota influencing the CTLA-4 blockade effect is similar to that of the PD-1 blockade. Bacteroides species play an important role in it. Fecal microbial transplantation from humans to mice confirmed that B. fragilis and B. thetaiotaomicron promote tumor CTLA-4 blockade reactivity by promoting the IL-12-dependent TH1 immune response [73].++++++++++
The mechanism by which favorable and unfavorable microbiota can regulate the efficacy of ICI in the intestinal tract has not been clearly reported, which may be related to the metabolic function of the microbiota. Favorable microbiota can synthesize a variety of metabolites that promote host immune function, while the catabolic function of unfavorable microbiota has the opposite effect [74]. In CRC model mice, inosine produced by the metabolism of B. pseudolongum was confirmed to enhance antitumor immunity induced by anti-CTLA-4 treatment, mediated by T cells [75]. In another study in mice, short chain fatty acids (SCFAs) produced by gut microbiota inhibited CD80/CD86 upregulation on dendritic cells induced by anti-CTLA-4 treatment, limiting the efficacy of anti-CTLA-4 in mice with metastatic melanoma [76]. The roles of favorable and unfavorable microbiota are not static. For example, in MSS-type CRC tumor-bearing mice, abundant Bacteroides would lead to increased Tregs and MDSCs in circulation and decreased CD8 T-cell infiltration in the tumor bed, which would decrease the cytokine response and the therapeutic effect of the PD-1 blockade [77]. Bacteroides has the role of promoting the therapeutic effect in the CTLA-4 blockade mentioned above [73], and the reason for the difference between the two remains to be discussed.+

3.2. Gut Microbiota and Antibiotic Use in ICI Therapy

In cancer patients, antibiotics are commonly used to prevent and treat a range of potentially life-threatening bacterial infections, which complicates cancer treatment and worsens the prognosis of patients with tumors [78][79][80]. It is a clinically obvious phenomenon that the long-term application of broad-spectrum antibiotics can lead to the irreversible destruction of gut microbiota ecology, which might result in diarrhea, double infection, and even the selection of drug-resistant strains [81][82][83]. In addition to increasing the complexity and difficulty of tumor treatment, dysregulated gut microbiota can also cause resistance to chemotherapy and immunotherapy in cancer patients [84][85]. A meta-analysis of 23 eligible studies showed that antibiotic use before or during ICI treatment resulted in a reduction in median OS for more than six months [86]. A retrospective study suggested that early use of antibiotics may be more harmful, while use of antibiotics during ICI treatment may be safer [87].
At present, it seems reasonable to avoid long-term and broad-spectrum antibiotics before starting ICI treatment, if possible. However, for some patients with malignant tumors, the use of antibiotics to prevent and treat infection is an irreplaceable choice because of long-term consumption and the decline of immunity [88][89]. For patients who do require antibiotics prior to ICI treatment, favorable strategies may be receiving FMT [68][90] or probiotics combined with dietary fiber therapy [91] in an attempt to eliminate the possible harmful effects of broad-spectrum antibiotics in ICI treatment. Another valuable direction would be to reduce the concentration of antibiotics in the gut without affecting their plasma pharmacokinetics. For example, nonspecific adsorbents can be applied to the patient’s intestine [92][93][94]. Oral β-lactamases target β-lactam antibiotics [95][96][97], significantly reducing the damaging effects of antibiotics on gut microbiota.

3.3. Gut Microbiota Affects the Efficacy of CAR T-Cell Therapy

Chimeric antigen receptor T (CAR-T) cell therapy refers to the modification of immunoreactive T cells derived from tumor patients with the chimeric antigen receptor (CAR), in vitro expansion, and then transfusion back into patients. The aim is to establish a long-term specific antitumor immune effect [98]. Therapeutic efficacy is usually limited by treatment-related toxicity, T-cell dysfunction, the TME, tumor antigen loss, and other reasons [99]. Antibiotic use is closely related to CAR-T efficacy, which is mediated by gut microbiota. In mice treated with broad-spectrum antibiotics, the tumor-suppressive effect of CAR-T was decreased [69]. Vancomycin-treated mice were more responsive than untreated mice to CAR-T treatment because vancomycin-screened gut microbiota induced an increase in systemic CD8α + DC and maintained adoptively transferred antitumor T cells in an IL-12-dependent manner [100].
The efficacy of CAR-T is affected by lymphocyte infiltration in the TME and the function of effector molecules. Vancomycin treatment increased the levels of granzyme B, perforin 1, IL-12, and IFN-γ in the TME of mice, which are all antitumor effector molecules [100]. The expression of antitumor effector molecules is affected by the metabolites of gut microbiota. Butyrate affects the gene expression of effector molecules by inhibiting histone deacetylase (HDAC) in CD8 T cells. Higher concentrations of acetate can promote IFN-γ production by CD8 T cells by regulating cell metabolism and mTOR activity, both of which affect the efficacy of CAR-T in mice [101]. In addition to effector molecules, gut microbiota can also modulate tumor-infiltrating lymphocytes (TILs). In human CRC, the gut microbiota stimulates tumor cells to produce chemokines to recruit antitumor T cells into the tumor tissue. Among them, the abundance of Rikenellaceae, Ruminococcace, and Lachnospiracee is significantly correlated with the expression levels of chemokines CCL5, CCL20, and CXCL11 [102].
A better understanding of the mechanisms by which the gut microbiome regulates the effects of CAR-T and ICI therapies will help maximize the effectiveness of immunotherapies in the future and reduce immunotherapy-related side effects [103]. A serious side effect of CTLA-4 blockade is autoimmunity, inducing severe inflammation. An experiment on mice showed that Bifidobacterium can relieve the toxicity of CTLA-4 blockade by affecting the metabolic function of Treg cells without affecting antitumor immunity [104]. Many immunotherapy strategies have been practiced and validated in experiments or clinical practice. More attention has been paid to the relationship between gut microbiota and antitumor immunotherapy. However, the role of gut microbiota in other immunotherapies, such as cytokine therapy and immune vaccines, remains poorly investigated. 

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Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Yunbo He
,
Jinliang Huang
,
Qiaorong Li
,
Weiping Xia
,
Chunyu Zhang
,
Zhi Liu
,
Jiatong Xiao
,
Zhenglin Yi
,
Hao Deng
,
Zicheng Xiao
,
Jiao Hu
,
Huihuang Li
,
Xiongbing Zu
,
Chao Quan
,
Jinbo Chen
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Revisions: 2 times (View History)
Update Date: 24 Nov 2022
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