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Microbial metabolites affect tumor progression, immunity and therapy prediction by reshaping the tumor microenvironment (Review)

  • Authors:
    • Yuhang Zhou
    • Wenjie Han
    • Yun Feng
    • Yue Wang
    • Tao Sun
    • Junnan Xu
  • View Affiliations

  • Published online on: June 6, 2024
  • Article Number: 73
  • Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Several studies have indicated that the gut microbiome and tumor microbiota may affect tumors. Emerging metabolomics research illustrates the need to examine the variations in microbial metabolite composition between patients with cancer and healthy individuals. Microbial metabolites can impact the progression of tumors and the immune response by influencing a number of mechanisms, including modulation of the immune system, cancer or immune‑related signaling pathways, epigenetic modification of proteins and DNA damage. Microbial metabolites can also alleviate side effects and drug resistance during chemotherapy and immunotherapy, while effectively activating the immune system to exert tumor immunotherapy. Nevertheless, the impact of microbial metabolites on tumor immunity can be both beneficial and harmful, potentially influenced by the concentration of the metabolites or the specific cancer type. The present review summarizes the roles of various microbial metabolites in different solid tumors, alongside their influence on tumor immunity and treatment. Additionally, clinical trials evaluating the therapeutic effects of microbial metabolites or related microbes on patients with cancer have been listed. In summary, studying microbial metabolites, which play a crucial role in the interaction between the microbiota and tumors, could lead to the identification of new supplementary treatments for cancer. This has the potential to improve the effectiveness of cancer treatment and enhance patient prognosis.

1. Introduction

A recent statistical survey indicated that there were almost 20 million new cases of cancer worldwide in 2022, with 9.7 million deaths attributed to cancer (1). Cancer has therefore emerged as a prominent factor contributing to human mortality. In recent decades, novel approaches for the prevention and treatment of cancer, including antibody-drug conjugates and immunotherapy (2-4), have been discovered. Although these therapeutic techniques have provided new opportunities for tumor treatment, their effectiveness is hindered by the resistance of tumor cells to drugs and the intricate structure of the tumor microenvironment (TME), which provides challenges in treating tumors (5,6). The irregularity of vascular networks within the TME can impede the transport of chemotherapeutic agents. Additionally, immunosuppressive cells within the TME have the capability to dampen immune responses, thereby attenuating the efficacy of immunotherapy. Exploring novel adjuvant therapy drugs is intended to improve the effectiveness of current treatments, ease patient distress and even achieve a cancer cure.

A recent study found that a lack of microbiota within the TME inhibits the production of type I interferon (IFN-I) by monocytes, thereby inducing M2 polarization of macrophages (7). This results in the formation of an immunosuppressive TME, which enables tumor cells to avoid being detected and destroyed by the immune system. Disruption of the microbiota has an impact on the advancement of tumors, but the restoration of imbalances in gut microbial composition through fecal microbiota transplantation (FMT) has been proposed as a promising approach for tumor treatment (8). The microbiota also promotes cancer by inducing chronic inflammation. When Ackermannia mucinophila is lost in the gut, the intestinal barrier function is disrupted, resulting in liver inflammation and fibrosis (9). Prolonged inflammation and fibrosis can gradually lead to aberrant hepatocyte proliferation and injury, potentially culminating in the development of hepatocellular carcinoma. Tumor progression and the microbiome are strongly interconnected through a number of pathways. For instance methylobacterium contributes to the development of gastric cancer by decreasing the production of TGF-β and CD8+ tissue-resident memory T-cells (10). Candida albicans promotes the secretion of interleukin (IL)-7, which promotes the release of IL-22 from RORγt+ (group 3) innate lymphoid cells (ILC3s) by activating the aryl hydrocarbon receptor (AHR) and STAT3 (11). IL-22 can promote tumor cell metastasis and the formation of intratumoral blood vessels (12,13). In summary, there have been an increasing number of studies that specifically investigating the relationship between the microbiome and cancer.

Microbes colonize numerous parts of the body (including tumors) and influence host tumorigenesis and tumor progression (14-17). Microbial metabolites, which are compounds produced during the growth and metabolic processes of microorganisms, have also been associated with the development of cancer (18). Gut bacteria convert primary bile acids into secondary bile acids, and elevated concentrations of secondary bile acids facilitate the proliferation of tumors by impairing the function of natural killer T-cells (19). In addition, some microbial metabolites are directly carcinogenic. For instance, cytotoxin-associated gene A produced by Helicobacter pylori induces BRCAness (the tumor exhibits characteristics associated with mutations in the BRCA1 or BRCA2 genes), promotes DNA double-strand breaks and induces bacteria-associated gastric cancer (20). In addition to causing cancer, some microbial metabolites may have anticancer effects. Reuterin, which is produced by Lactobacillus reuteri, selectively oxidizes proteins and inhibits ribosomal biogenesis and protein translation to restrict the proliferation and survival of colon cancer cells (21). In summary, microbial metabolites play a role in the development and advancement of tumors through several processes. Targeting these metabolites may therefore offer additional advantages in treating patients, such as enhanced therapeutic efficacy, reduced adverse effects and overcoming drug resistance.

Microbial metabolites can potentially serve as supplementary therapeutic agents to enhance current clinical techniques. Gut microbial metabolism produces butyric acid, which regulates the T-cell receptor signaling pathway to stimulate the generation of cytokines that possess antitumor effects (22). Butyric acid notably improves the antitumor capacity of immune cells, leading to improved effectiveness of anti-programmed cell death protein 1 (PD-1) immunotherapy. Microbial metabolites have a reciprocal impact on clinical therapy. The metabolism of Fusobacterium nucleatum results in the production of succinic acid, which hampers the synthesis of IFN-β and restricts entry of CD8+ T-cells into the TME. As a result, the immune response against the tumor is suppressed (23). Therefore, microbial metabolites may have a dual impact, exerting both beneficial and harmful impacts on tumor treatment. To fully understand the dual impact, it is crucial to not only clarify its exact mechanism of action but also to consider the specific environment in which it produces its effects. Varying amounts of short-chain fatty acids (SCFAs) yield diverse outcomes in the therapy of tumors. In non-alcoholic fatty liver disease, high levels of SCFAs (when the concentration exceeds the threshold of host tolerance) leads to the progression of hepatocellular carcinoma (24). However, when present in normal amounts, SCFAs markedly hinder the advancement of colorectal cancer (25). Thus, the effect of microbial metabolites on tumors is not absolute, and different microbial metabolites have different effects at different concentrations.

The present review explores the functions and mechanisms of various microbial metabolites in the development of tumors, the advancement of tumors and the immune response to tumors. The impact of microbial metabolites on chemotherapy and immunotherapy are also investigated, providing a detailed explanation of the underlying mechanisms. The present review also evaluates the potential of microbial metabolites as supplementary therapeutic agents for cancer and suggests future research areas for microbial metabolites in the field of oncology.

2. Microbial metabolites remodel the TME to promote tumor progression

Tumors are not only composed of a simple set of tumor cells but also infiltrate and host a diverse set of host cells, cytokines and extracellular matrices (26-28). Consequently, throughout the process of tumor formation, tumor cells frequently utilize various tactics to influence both themselves and the neighboring cells. This fosters a favorable environment for the proliferation and metastasis of tumor cells. Research has indicated that tumor cells increase the concentration of lactate at the tumor location by employing glycolysis. The buildup of lactate is frequently linked to a reduction in the immune response against the tumor within the TME (29). Meanwhile, these lactates also serve as signaling molecules in both autocrine and paracrine mechanisms within the tumor, activating G protein-coupled receptor (GPR) 81 (30). Activation of GPR81 promotes angiogenesis and immune evasion within the TME. In pancreatic cancer, CD73 mediates activation of the p38/STAT1 axis by inducing extracellular adenosine accumulation, leading to the upregulation of C-C motif chemokine ligand (CCL) 5 transcription, which attracts regulatory T cells into the TME (31). Therefore, tumor cells exert an influence on the advancement of tumors by altering the programming of the TME. As the tumor advances, microbial metabolites are generated by microorganisms in the tumor and stored in the TME. These microbial metabolites will function as ligands for specific receptors or as cytokines to regulate the activity of proteins and modify the TME. Research has shown that in mice with colon cancer, microbial metabolism leads to high levels of intestinal ammonia, which induces metabolic reprogramming of T cells, increasing T cell exhaustion and decreasing its proliferation (32). Administering streptomycin to animals with breast cancer results in a reduction in the abundance of lactobacilli in the intestinal tract. The proportion of CD4+ and CD8+ T cells that produce IFN-γ is decreased in the TME. Nevertheless, following the administration of lactobacilli, there is an augmentation in the lactic acid content at the location of the tumor, resulting in the disappearance of this phenomenon (33).

Therefore, microbial metabolites can facilitate the advancement of tumors by altering the TME. Byproducts of the microbial community in the gut and the microorganisms associated with tumors have a role in the advancement of tumors and long-lasting inflammation. Fig. 1 illustrates how gut microbiota, as well as intratumoral microbiota, and their metabolites collectively reprogram the TME. Additionally, Fig. 1 outlines the mechanisms by which lipopolysaccharides (LPSs), SCFAs and secondary bile acids inhibit tumor immunity and induce chronic inflammation.

Figure 1

Mechanisms by which various microbial metabolites cause tumor progression and chronic inflammation. The TME is a complex system composed of immune cells, tumor cells, cytokines and blood vessels. Various metabolites enter the TME, affecting the activities of various internal cells and regulating the release of cytokines, thereby reshaping the TME to promote tumor progression. LPS activates the NF-κB signaling pathway in prostate cancer, promoting the release of IL-6. The binding of LPS and TLR4 on colorectal cancer cells promotes VEGF secretion. LPS activation of TLR4 induces macrophages to upregulate CCL5 expression. LPS can cause chronic inflammation, leading to the accumulation of MDSCs and Tregs. SCFAs promote the differentiation of CD4+ T cells into Th17 cells and the release of IL-17. SCFAs stimulate prostate cancer cells to secrete IGF-1. The accumulation of SCFAs promotes high expression of FPR on the surface of breast cancer cells. The accumulation of LCA upregulates CCL 28 and IL-8 by activating the GPR and Erk1/2 MAPK signaling pathways. 3-oxo LCA and isoallo LCA respectively inhibit the differentiation of Th17 cells and promote the differentiation of Treg cells. DCA binds to VEGFR2 to promote EMT and VM, while also promoting the differentiation of CD4+ T cells into Tregs. The figure was created using TME, tumor microenvironment; LPS, lipopolysaccharide; IL, interleukin; TLR, toll-like receptor; VEGF, vascular endothelial growth factor; CCL,C-C motif chemokine ligand; MDSCs, myeloid-derived suppressor cells; Treg, regulatory T cell; SCFAs, short-chain fatty acids; Th, T helper; IGF, insulin-like growth factor; FPR, formyl peptide receptor; LCA, lithocholic Acid; GPR, G-protein coupled receptor; DCA, deoxycholic acid; VEGFR, VEGF receptor; EMT, epithelial-mesenchymal transition; VM, vasculogenic mimicry.


LPS is an essential component of the cell wall in Gram-negative bacteria (GNB). An examination conducted in 2020 on bacterial populations present in pan-cancerous tumors demonstrated that LPS has a crucial role in promoting inflammation in different types of cancer (34). Using polymyxin B to clear GNB from the intestines or using TAK-242 to block LPS activation of Toll-like receptor 4 (TLR4) can both alleviate the immunosuppressive microenvironment of colorectal cancer and facilitate T-cell infiltration into the tumor (35). Thus, LPS has the potential to trigger long-term inflammation, leading to the advancement of cancer. Long-term inflammation caused by LPS results in T-cell exhaustion, an increase in the expression of the PD-1/programmed death-ligand 1 (PD-L1) axis and the buildup of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). This leads to the development of a microenvironment that suppresses the immune system and promotes the proliferation and advancement of tumors (36).

Furthermore, LPS promotes the secretion of various cytokines that aid in tumor cell proliferation and metastasis. Activation of the NF-κB signaling pathway by LPS results in the secretion of IL-6, which activates STAT3 in an autocrine manner., promoting prostate cancer progression in mice (37). LPS also stimulates TLR4 to induce the expression of vascular endothelial growth factor (VEGF) C, which promotes tumor cell metastasis and lymphangiogenesis (38). Macrophages, which are integral components of the TME, exert a marked influence on the evasion of the immune system by tumors. Research has shown that stimulation of the TLR4 signaling pathway by LPS leads to an increase in the production of CCL5 by macrophages. Consequently, this obstructs the ability of T cells to destroy colorectal cancer cells and enables the cancer cells to avoid detection by the immune system. In addition, CCL5 regulates the process of removing ubiquitin molecules from PD-L1 and maintaining its stability (39).


SCFAs have been shown to possess antitumor capabilities (40). However, SCFAs may also promote tumor progression and metastasis via immunomodulatory effects, signal transduction regulation and inflammation modulation, all of which can remodel the TME. In the intestine of gnotobiotic mice colonized with the F. nucleatum Fn7-1 strain, Fn7-1 metabolism produces SCFAs that combine with GPR43 to increase colonic T helper 17 (Th17) cell frequency and promote IL-17A and IL-17F expression, which leads to chronic inflammation and increases the risk of colorectal cancer (41). Furthermore, SCFAs enhance the activation of the MAPK and PI3K signaling pathways in the neighboring prostate region by upregulating the production of insulin-like growth factor-1, hence facilitating the proliferation and multiplication of prostate cancer cells (42). The most prevalent SCFAs in the human body include acetic acid, propionic acid and butyric acid. Although the majority of studies concentrate on these three molecules, it is crucial not to disregard the potential influence of formate on the advancement of tumors. Genetic interference has been found to effectively decrease tumor cell invasion by inhibiting the synthesis of formate (43). Additionally, the accumulation of formate has been shown to increase the expression of the formyl peptide receptor, which enhances the invasive ability of cancer cells (44). Formate also plays a role in promoting colorectal cancer tumor invasion and enhancing the population of tumor stem cells through the activation of AHR signaling (45). Formate treatment induces a rise in Th17 levels (45), which are inflammatory regulatory cells that promote chronic inflammation. Therefore, formate may enhance the progression of colorectal cancer by promoting chronic inflammation.

Secondary bile acids

When considering the relationship between secondary bile acids and different tumor types, including colorectal cancer and liver cancer, it is important to investigate therapeutic approaches involving secondary bile acids to advance the prevention and treatment of these tumors (46,47). The gut microbiome produces bile salt hydrolases (BSHs) to deoxygenate primary bile acids into secondary bile acids, primarily deoxycholic acid (DCA) and lithocholic acid (LCA). These compounds can contribute to tumor progression by reshaping the TME (48). Unconjugated DCA and LCA buildup in the intestine and stimulate GPRs in regions where BSH is highly expressed. As a result of this activation, there is an elevated production of CCL28, which is regulated by β-catenin, in the tumor. Activation of the β-catenin/CCL28 axis leads to increased amounts of Tregs in the TME, which in turn creates an immunosuppressive microenvironment (49). In Apcmin/+ mice (a commonly used mouse model for colon cancer), the accumulation of DCA activates VEGF receptor 2, promoting vasculogenic mimicry and epithelial-mesenchymal transition (EMT) (50).

Additionally, secondary bile acids also induce the expression of cytokines that influence tumor progression. LCA activates Erk1/2 MAPK and inhibits STAT3 phosphorylation to promote IL-8 expression in colorectal cancer cells (51). LCA induces the progression and metastasis of colorectal cancer via promoting IL-8 expression (52). Furthermore, DCA activates CD4+ T cells and induces IL-10 secretion to induce Treg cell differentiation, causing an immunosuppressive microenvironment (53). Furthermore, the release of IL-10 stimulates the polarization of tumor-associated macrophages (TAMs) towards the M2 phenotype, hence facilitating the proliferation and metastasis of colorectal cancer (54). The two derivatives of LCA are 3-oxo LCA and isoallo LCA. 3-oxo LCA hinders Th17 cell differentiation by binding to retinoid-related orphan receptor-γt, whereas isoallo LCA encourages the formation of Tregs by producing mitochondrial reactive oxygen species (ROS) (55).

3. Microbiota modulates tumor immunity by producing relevant metabolites

Studies suggest that the microbiome can improve disease control in individuals with tumors (56-58). A study found that FMT improved the effectiveness of anti-PD-1 therapy in mice with colorectal cancer (59). Another study demonstrated that FMT altered the cellular constitution within the TME of patients with melanoma, helping to surmount resistance to anti-PD-1 therapy (60). The TME is colonized by a diverse range of microbes, but its complex composition restricts the manipulation of the microbiota. Microbial metabolites can be utilized to provide a more accurate control of the immune response in the TME, offering novel approaches for tumor research and treatment. For instance, a recent study aimed to examine the effects of the bacterial-derived metabolite, desaminotyrosine (DAT), on C57BL/6J mice. The results demonstrated that the group treated with a combination of DAT and anti-CTLA-4 had a higher immunotherapy response compared with the group that received only anti-CTLA-4 (61).

The success of immune checkpoint inhibitors (ICIs) in tumor therapy significantly relies on reactivating specific T cells and promoting the apoptosis of Tregs present within the TME (62,63). Therefore, it is highly probable that microbial metabolites can alter tumor immunity by reprogramming the TME. Alleviating the persistent inflammatory response in the TME could potentially facilitate the development of a beneficial immune microenvironment, and hence enhance the response of the immune system to the tumor. Moreover, activation of the immune system is essential for enhancing tumor immunity. Fig. 2 illustrates how trimethylamine N-oxide (TMAO), SCFAs and Trp-related metabolites promote antitumor immunity by reprogramming the TME and outlines the mechanisms through which they exert their effects.


TMAO has been linked to a range of diseases, such as cardiovascular disease and liver, pancreatic and colorectal cancer (64-67). While the exact method by which TMAO contributes to tumor progression remains unclear, it is known that elevated levels of amines, as a metabolite, lead to oxidative stress (68). Oxidative stress can lead to an increase in intracellular DNA mutations and genomic instability, which in turn promotes cancer incidence and tumor progression. Recently, several investigations have established a connection between TMAO and different cancer types. For instance, TMAO produced by the gut microbiota during the breakdown of food has been found to stimulate macrophages, enhance the response of T cells and decrease the number of tumor cells in pancreatic ductal adenocarcinoma (PDAC) by increasing the production of IFN-Ⅰ (66). Due to the connection between the pancreatic duct and the duodenum, microbial metabolites from the intestines can reach the pancreatic duct and surrounding tissues. This could potentially have a role in the development and treatment of PDAC. Immunotherapy has had little effectiveness in treating triple-negative breast cancer (TNBC) (69). A study that conducted a multi-omics analysis of patients with TNBC discovered that TMAO was linked to a cohort that received immunotherapy and exhibited an improved immune response. TMAO also triggers tumor cell pyroptosis by activating the endoplasmic reticulum stress kinase, PERK, while also boosting CD8+ T cell-driven antitumor immunity in the host (70). Meanwhile, a study revealed a correlation between elevated blood levels of TMAO and colorectal cancer (71). However, the precise pathophysiology remains uncertain, but it is likely associated with the stimulation of persistent gastrointestinal inflammation. Hence, it is crucial to regulate the concentration of TMAO when employing TAMO for research or cancer therapy. Several strategies, including the suppression of crucial metabolic enzymes, dietary regulation and the use of antibiotics, have been suggested to manipulate the gut microbiome to produce TMAO (72-74).


SCFAs are important metabolites generated by the intestinal microbiota during the digestive process, mainly consisting of acetic acid, propionic acid and butyric acid. SCFAs promote the metabolism of intestinal epithelial cells and enhance the intestinal barrier function (75). Certain research suggests that increasing the levels of butyric acid in the stomach through pectin supplementation can promote the infiltration of T cells in the TME and improve the efficacy of ICIs in treating colorectal cancer (76). SCFAs have shown strong antitumor effects in multiple types of cancer, particularly colorectal cancer (77). The ability to act through different routes is made possible by the diversity of SCFAs and their derivatives. The antitumor actions of SCFAs are achieved through their binding to many GPRs, such as GPR41, GPR43 and GPR109a. Through the gut-hepatic axis, acetic acid binds to GPR43 in the liver, limiting IL-6 release and obstructing the JAK1/STAT3 signaling pathway to stop liver cancer from progressing (78). Moreover, a study found that the combination of propionic acid and GPR43 also inhibited the proliferation of liver cancer cells (79). In addition, propionic acid can inhibit the Hippo/Yap and MAPK signaling pathways by binding to GPR41 and GPR43, ultimately inhibiting the metastasis of breast cancer cells (80). Butyric acid acts on GPR109a in colon macrophages and dendritic cells, inducing the differentiation of Tregs and CD4+ T cells and inhibiting the development of colitis and colorectal cancer (81). Moreover, a study has shown that GPR43 deletion accelerates the development of colorectal cancer by exhausting CD8+ T cells and hyperactivating dendritic cells (82). In summary, SCFAs stimulate the proliferation and specialization of immune cells by attaching to GPRs. SCFAs also hinder the advancement and metastasis of tumors by attaching to GPRs on tumor cells. Additionally, SCFAs suppress long-term inflammation by activating GPR signaling, which prompts the development of Tregs.

Tumor progression has been closely linked to epigenetic reprogramming. Tumor cells frequently exhibit elevated levels of histone deacetylases (HDACs), which lead to increased histone deacetylation. This alteration affects the control of gene expression and facilitates the advancement and metastasis of tumors (83). Additionally, HDACs suppress both the immune response and inflammatory events in immune cells (84). HDAC inhibitors enhance the antitumor therapeutic efficacy of ICIs by modifying the immunosuppressive function of TAMs and impeding the ingress of MDSCs into tumors, thereby remodeling the immunosuppressive microenvironment (85). In a recent study, inhibition of HDAC by butyric acid caused an elevation in CD25 expression, INF-γ and tumor necrosis factor-α and greatly enhanced the antitumor function of cytotoxic T lymphocytes in pancreatic cancer and melanoma models (86). Propionic acid also inhibits IL-17 and IL-22 secretion by γδ T-cells via inhibition of HDAC, which could inhibit colitis-associated colorectal cancer development (87). A study has also demonstrated that butyric acid inhibits the growth and promotes the apoptosis of P815 mouse breast cancer cells by inhibiting HDAC, in addition to the effects of SCFAs on immune cells (88).

Trp metabolites

The presence of Trp metabolites in organisms is influenced, either directly or indirectly, by the gastrointestinal microbiome. Metabolites and enzymes associated with Trp have been identified as prospective targets for pharmaceutical advancements in the treatment of various disorders, such as psoriasis, atopic dermatitis and hepatic fibrosis (89-91). Trp metabolites have been reported to act selectively on AHR (92). Indole-3-aldehyde (I3A) activates the AHR of CD8+ T cells in the melanoma TME, promoting CD8+ T-cell differentiation and IFN-γ production (93). This enhances ICI-induced antitumor immunity. However, in PDAC, Trp metabolites bind to the AHR of TAMs and reduce the frequency of intratumoral CD8+ T cells, creating an immunosuppressive microenvironment (94). This implies that the effects of Trp metabolite-mediated AHR activation may vary among tumor types or be influenced by heterogeneity in the TME.

Epigenetic modifications are of the utmost importance in the regulation of gene expression and are critical in the development, progression and treatment of numerous types of cancer. An examination of the effects that microbial metabolites have on epigenetic modifications will establish a solid theoretical basis for the advancement of novel approaches in the field of tumor immunotherapy. Tumor immunity can be regulated by Trp metabolites via epigenetic modifications. Indole-3-lactic acid alters chromatin accessibility to initiate the antitumor activity of CD8+ T cells and directly enhances the secretion of IFN-γ and granzyme B by tumor-infiltrating CD8+ T cells to kill tumor cells, and also promotes IL-12a secretion by binding to dendritic cells (95). IL-12a in turn further induces the proliferation of CD8+ T cells and promotes tumor immunity (96).

A modest elevation in oxidative stress and suppression of EMT can greatly impede the growth and metastasis of tumor cells. Indoxylsulfate (IS) suppresses the activity of nuclear factor erythroid 2-related factor 2 and stimulates the production of inducible nitric oxide synthase, leading to the occurrence of oxidative and nitrosative stress. Additionally, IS hinders EMT, resulting in a notable decrease in the metastasis of breast cancer cells to adjacent tissues (97). The metabolism of Trp is not only regulated by the gut microbiome but also by tumor cells (98). Tumor cells often exhibit heightened activity in Trp metabolic pathways, such as indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase, which facilitate the conversion of Trp into kynurenine. This process increases the number of Tregs in the TME and boosts the expression of PD-1 on CD8+ T cells, helping tumor cells avoid detection by the immune system (99). An extensive examination of the regulatory mechanisms of Trp metabolism will provide new targets and strategies for tumor therapy, given the intricate nature of the Trp metabolic pathway.

4. Impact of microbial metabolites on clinical cancer therapy

At present, a substantial percentage of individuals diagnosed with cancer undergo radiotherapy as part of their treatment. While a number of individuals have experienced positive outcomes from radiotherapy, it can nevertheless result in various negative effects. For instance, research has demonstrated that whole-brain radiotherapy administered to patients with lung cancer and brain metastases will ultimately result in memory impairment (100). A retrospective cohort study found that patients with nasopharyngeal carcinoma had a higher incidence of oral mucositis during radiotherapy (101). The detrimental consequences of these side effects might significantly impair the quality of life of the patient and perhaps result in treatment discontinuation or decreased patient tolerance. The critical clinical problem of mitigating harmful effects in patients following radiotherapy is increasingly recognized. Evidence indicates that microbial metabolites possess the ability to alleviate detrimental effects on the host following exposure to ionizing radiation. Increased concentrations of propionate and Trp metabolites, which show long-term radioprotection, were found in the intestines of mice that received high doses of radiation but maintained a normal lifespan (102). Meanwhile, DCA can be used to treat radioactive skin injuries, promote wound healing and reduce epidermal hyperplasia (103). As a result, microbial metabolites are important in cancer therapy, and an increasing number of studies are investigating the potential applications of microbial metabolites to enhance therapeutic outcomes or minimize side effects in patients with cancer (104-106). The role of microbial metabolites in immunotherapy and chemotherapy are the focus of this section. Table I presents clinical trials regarding LPS, SCFAs and urolithin A (UroA), aimed at investigating the role of microbial metabolites in cancer treatment. Table II presents experimental and observational clinical trials of gut microbiota to explore their impact and mechanisms in cancer treatment.

Table I

Current list of clinical trials on microbial metabolites in various types of cancer, according to

Table I

Current list of clinical trials on microbial metabolites in various types of cancer, according to

Study IDDiseasePurposeNo of patientsInclusion criteriaStudy state
NCT05751837CancerThe main objective is to activate the immune system by injecting LPS into abdominal tumors and evaluate its potential effects on tumor treatment.6 adultsParticipants must have at least two index non-visceral intra-abdominal tumors that are grossly visible, >1 cm3 in volume and amenable to biopsy and injection of investigational drug or control solution at the time of laparoscopy.Recruiting
NCT04700527CancerTo assess and compare GI toxicity from RT between subjects who receive therapeutic SCFA and those who receive placebo, identifying a safe, low-cost therapeutic to reduce GI toxicity from therapeutic or environmental radiation.122 adultsSubjects with histological or cytological evidence/confirmation of GI, urologic or gynecologic malignancy.Not yet recruiting
NCT06022822Prostate cancerThis phase II randomized control trial assesses the effect of Uro-A supplementation compared to placebo in men with biopsy-confirmed prostate cancer undergoing RP progressive disease.90 adultsParticipants must have pathologically confirmed adenocarcinoma of the prostate with FFPE biopsy tissue available for analysis. Diagnosis can be any time in the 6 months prior to registration or randomization.Not yet recruiting

[i] LPS, lipopolysaccharide; GI, gastrointestinal; RT, radiation therapy; SCFA, short-chain fatty acid; UroA, urolithin A; RP, radical prostatectomy; FFPE, formalin-fixed paraffin embedded.

Table II

Current clinical trials on relevant microorganisms in various types of cancer, according to

Table II

Current clinical trials on relevant microorganisms in various types of cancer, according to

Study IDDiseasePurposeNo. of patientsInclusion criteriaStudy state
NCT06039644Breast cancerTo explore after consumption of probiotics of lactobacillus composite strain powder sachets for 6 months in BC chemotherapy, and whether it assists patients in alleviating the side effects of chemotherapy.100 adultsStage I-III patients with BC receiving anthracycline-based and taxane-based chemotherapy (not limited to before or after chemotherapy/surgery).Not yet recruiting
NCT05725720Diffuse large B-Cell lymphomaInvestigate the potential impact of the GM on treatment response and prognosis in patients with DLBCL undergoing CAR-T cell therapy.90 adultsPatients diagnosed with histologically confirmed DLBCL who are eligible for CAR-T cell therapy based on clinical approval for commercial products.Recruiting
NCT05112614CancerThis study examines how GM can affect cancer therapy in patients with cancer undergoing cancer therapy or SCT. Information from this study may help doctors improve the way cancer treatment condition is delivered and increase its efficacy and success.5,000 adultsDiagnosis of cancer and undergoing cancer therapy or scheduled to start cancer therapy or undergoing stem cell transplant for any hematological.Recruiting

[i] BC, breast cancer; GM, gut microbiome; DLBCL, diffuse large B-cell lymphoma; CAR-T, chimeric antigen receptor T cell; SCT, stem cell transplant.


Chemotherapy is a popular cancer treatment that can halt cancer from progressing via several methods, but drug resistance and adverse effects remain a problem. As such, reducing the adverse effects and medication resistance linked to chemotherapy is a major task. As demonstrated in Fig. 3, the combined use of microbial metabolites and various chemotherapy drugs can regulate the TME through multiple mechanisms, promoting tumor cell apoptosis.

Figure 3

Outcome and underlying mechanism of the combined use of microbial metabolites and chemotherapeutic drugs. Microbial metabolites enhance the efficacy of chemotherapy drugs, promoting apoptosis of tumor cells. The combination of mitoxantrone and UroA downregulates the expression of drug-resistant proteins in breast cancer cells. The combination of 5-FU and UroA upregulates FOXO3 and inhibits FOXM1, promoting the apoptosis of tumor cells. The product of 3-IAA oxidized by MPO downregulates the synthesis of ROS-degrading enzymes, leading to ROS accumulation and enhancing the efficacy of 5-FU. Succinic acid increases the ratio of BAX/BCL-2 in tumor cells, promoting the antitumor ability of irinotecan. Irinotecan is metabolized by the liver into the inactive product SN-38G, which is hydrolyzed into the active product SN-38 by the G of intestinal bacteria. Although this enhances the side effects of irinotecan, it improves the efficacy against metastatic CRC. Succinic acid directly increases the chemosensitivity of CRC cells, enhancing the efficacy of oxaliplatin. Succinic acid also inhibits the expression of adhesion-related outer membrane proteins of Fusobacterium nucleatum, reducing its colonization in the intestine and enhancing the chemosensitivity of CRC cells. The figure was created using UroA, urolithin A; 5-FU, 5-fluorouracil; 3-IAA, indole-3-acetic acid; MPO, myeloperoxidase; ROS, reactive oxygen species; TME, tumor microenvironment; G, glucuronidase; CRC, colorectal cancer.

UroA is a product of gut microbial metabolism. UroA has been reported to downregulate the expression of breast cancer resistance protein (a drug efflux transporter protein), which would contribute to the sustained efficacy of mitoxantrone in cancer cells (107). Meanwhile, in a recent study, UroA and its structural analog, UAS03, were combined with the chemotherapeutic drug, 5-fluorouracil (5FU), and investigated for their anticancer effects. The results showed that UroA/UAS03 re-sensitized 5FU-resistant colorectal cancer to chemotherapy by modulating the FOXO3/FOXM1 axis (108). These findings indicate that the use of UroA in combination with low-dose chemotherapeutic drugs can provide similar antitumor effects as high-dose chemotherapeutic drugs, potentially minimizing the negative side effects associated with chemotherapy. Furthermore, UroA can suppress the growth of gastric cancer cells, hinder their capacity to invade and metastasize and stimulate their programmed cell death (109). This indicates that UroA may emerge as a novel adjuvant cancer therapy medication. However, further investigations are necessary to confirm the safety and effectiveness of UroA, as well as to identify the ideal therapeutic concentration and clinical protocol.

Butyrate is a SCFA produced by gut microbiota, typically generated as a byproduct during the fermentation of dietary fibers in the colon. Butyrate has demonstrated potential efficacy as an adjuvant treatment drug in chemotherapy by modulating cellular metabolism, reducing oxidative stress and preserving liver function through various mechanisms (110-112). The coadministration of butyrate and irinotecan induces programmed cell death in colorectal cancer cells by modulating the BAX/BCL-2 ratio, while also augmenting the responsiveness of cancer cells to irinotecan (113). Meanwhile, butyrate and oxaliplatin can synergistically inhibit the proliferation, invasion and metastasis of colorectal cancer cells and promote the apoptosis of these cells (114). Furthermore, the intestinal bacterium, F. nucleatum, promotes resistance to chemotherapy in colorectal cancer by modulating autophagy (115). Butyrate downregulates the expression of adhesion-associated outer membrane proteins and inhibits F. nucleatum growth, enrichment and adhesion in colorectal tissues, thereby reducing F. nucleatum colonization and mitigating F. nucleatum-induced chemoresistance (116). Gut microbiota can produce indole-3-acetic acid (3-IAA) by metabolizing tryptophan from the diet. Neutrophil-derived myeloperoxidase (MPO) is essential for the joint action of 3-IAA and chemotherapy. MPO catalyzes the oxidation of 3-IAA. When combined with chemotherapeutic drugs, the oxidative products of 3-IAA can reduce the production of enzymes that degrade ROS. This leads to an increase in ROS levels and a decrease in tumor cell autophagy, ultimately inhibiting the development of tumor cells (117). Therefore, appropriate intervention in the nutrition of patients with cancer during treatment may have a positive impact on chemotherapy.

Microbial metabolites can both increase and impair the efficacy of chemotherapy. A study has demonstrated that Lactobacillus residing in tumors can lead to resistance to radiotherapy and chemotherapy. This resistance is achieved by modifying the metabolism of the tumor and the signaling pathways related to lactate (118). Furthermore, the metabolites produced by microbes as they metabolize chemotherapy drugs can lead to undesirable responses. A randomized controlled trial conducted in 2021 revealed that bacterial glucuronidase can break down the inactive metabolite of irinotecan, SN-38G, into its active form, SN-38. This process subsequently leads to damage in the intestinal mucosa (119).


ICIs have been used with great success in cancer treatment, but many adverse effects (such as gastrointestinal reactions) that occur during treatment have limited their wider application (120). Nevertheless, the integration of ICIs with microbial metabolites could potentially resolve this issue. I3A was found to have a protective impact on enteritis generated by ICIs in mice. Additionally, I3A protected enteritis induced by ICIs in mice that received FMT from I3A-treated mice via modifying the composition and function of the gut microbiome (121). The TME consists of a complex network of various cytokines, immune cells and cancer cells. Fig. 4 illustrates that UroA, SCFAs, LPS and inosine act on components of the TME to activate the immune system and promote the transition from a 'cold' TME (TME lacking immune cell infiltration and activity) to a 'hot' TME, thereby enhancing the efficacy of immunotherapy.

At present, a considerable proportion of individuals with cancer do not demonstrate a strong reaction to ICI therapy due to cancer cells employing various strategies to avoid detection by the immune system (122-125). Therefore, activation of immune cells within the microenvironment has become a crucial research avenue to enhance the efficacy of ICIs. In a recent study, UroA alone led to a notable decrease in M2-like macrophages and an elevation in CD4+ and CD8+ T-cell infiltration within the TME, as well as downregulation of PD-1 expression and a rise in the overall survival rate of mice with cancer (126). Moreover, the reciprocal impacts of microbial metabolites can potentially lead to a reduction in the effectiveness of ICIs. Despite their anticancer properties, SCFAs hinder the effectiveness of anti-CTLA-4 antibodies in treating melanoma. This is due to their ability to decrease the presence of tumor-specific and memory T cells, while simultaneously boosting the proportion of Tregs (127).

Prior research has demonstrated that cytokines exert influence on the proliferation, progression and therapeutic interventions of cancer by regulating the function of both immune cells and tumor cells. Tumors with excessively active cytokine signaling pathways frequently experience increased tumor proliferation and invasion, significantly reducing the effectiveness of ICIs (128-130). Targeted binding against cytokines and their receptors may also leading to new strategies for tumor therapy (131-133). Microbial metabolites may indirectly influence the efficacy of ICIs by modulating cytokines. LPS upregulates IL-6 levels, which leads to tumor cell proliferation by activating JAK/STAT signaling (134). Furthermore, elevated levels of IL-6 in the TME not only diminishes the effectiveness of ICIs but also intensifies the negative side effects caused by ICI treatment (135). In addition, IL-12 can reprogram the TME, directly bind to the IL-12 receptor on CD8+ T cells and activate these cells, while promoting the infiltration of CD4+ T cells and downregulating the number of Tregs, which ultimately significantly improves the efficacy of ICIs (136,137). A variety of microbial metabolites modulate IL-12 secretion. Research has shown that LPS induces IL-12 secretion, which is inhibited by butyrate (138).

In summary, microbial metabolites can modify the immunological status of the TME, converting it from a 'cold' to a 'hot' environment, and control the relative amounts of different cytokines, all of which will increase the effectiveness of ICIs. Microbial metabolites also have the potential to influence cytokine receptors in addition to immune cells and cytokines. It has been found that inosine binds to A2A in the presence of exogenous IFN-γ to promote the differentiation of Th1 cells and significantly increase the expression of the IL-12 receptor and IFN-γ in Th1 cells, which may effectively improve the efficacy of ICIs (139).

5. Conclusions, limitations and future directions

The present review examined the relationship between microbial metabolites and cancer based on previous studies, specifically focusing on two aspects: Tumor therapy and tumor progression. Microbial metabolites exert dual impacts on tumors. Microbial metabolites impact tumor development by reprogramming the TME, which involves altering the makeup of immune cells and the expression of cytokines. Microbial metabolites also enhance tumor cell proliferation, invasion and metastasis by influencing a number of signaling pathways, resulting in increased tumor cell growth. The present review also summarized the impact of microbial metabolites on current cancer treatments and described the mechanisms by which microbial metabolites influence treatment efficacy. In this context, microbial metabolites again exhibit dual effects. Microbe-derived metabolic products have the potential to improve the outcomes of immunotherapy, chemotherapy and radiation, and can also strengthen the immune system in patients with cancer, lessen the negative effects of drugs and fight drug resistance. Meanwhile, by promoting the immunosuppressive TME, microbial metabolites can also lessen the effectiveness of therapies.

There is a limitation in the current review of microbial metabolites and cancer, as research on gut microbiota metabolites is primarily focused on colorectal cancer, resulting in previous reviews being confined to the impact of microbial metabolites on colorectal cancer. However, in the present review, studies on colorectal cancer were not only examined but research on the association between microbial metabolites and other cancer types such as melanoma, breast cancer, liver cancer and pancreatic cancer, were also included (140-142). Furthermore, in reviews concerning microbial metabolites and cancer, researchers tend to focus more on summarizing the connection between microbial metabolites and antitumor immunity, while overlooking the negative impact that microbial metabolites may also have in promoting tumor progression. In contrast to previous reviews, the present review supplements the understanding of the influence of microbial metabolites on tumor progression (143). With the rapid advancement of immunotherapy, reviews focusing on microbial metabolites have increasingly emphasized their impact on immunotherapy. However, considering the high cost of immunotherapy, the majority of patients with cancer still undergo chemotherapy and radiation therapy. Therefore, research on microbial metabolites in the fields of chemotherapy were further explored to assess their potential in mainstream cancer treatments (144). However, the present review has limitations. Given that clinical trials investigating microbial metabolites are currently either recruiting or are in the experimental stages, clinical trial results were not reviewed to assess the potential of microbial metabolites as adjunctive cancer therapeutics.

In recent decades, cancer has come to be seen as a serious threat to the safety of human life. Nonetheless, cancer treatment has proven to be difficult due to the intricate and varied characteristics of the TME. To find a solution, scientists are continuously experimenting with novel approaches and enhancing current therapies. As research on the gut microbiome continues, researchers are beginning to recognize that there is a significant relationship between the gut microbiome and cancer. Scientists have found microbial colonization within the TME, attributed to the rapid progress of next-generation sequencing technologies and analytical resources. The metabolites of this group of bacteria do not require the employment of various intricate transporters to reach the tumor. Instead, they directly release metabolites, resulting in the heterogeneity of the TME. However, additional research is necessary to clarify the relationship between microbial metabolites and cancer. Advancements in this area will provide new research ideas and therapeutic strategies for the prevention and control of cancer.

Prior research has discovered microbial metabolites that impact tumor treatment and advancement by influencing the immune system of the patient, cancer or immune-related signaling pathways, protein epigenetic alteration and DNA damage. Notably, microbial metabolites have dual impacts on both tumor development and tumor immunology. As a result, developing a more intricate comprehension of microbial metabolites will facilitate their utilization as supplementary therapeutic agents, as well as in conjunction with anticancer drugs, thereby enhancing effectiveness. Furthermore, recent studies have focused on the influence of certain microbial metabolites on cancer, with particular emphasis on metabolites that exhibit notable disparities in metabolomics analysis. This could potentially neglect the significant contribution of other metabolites or the combined and opposing impacts of metabolites.

Future research should aim to gain a comprehensive understanding of the processes by which microbial metabolites operate in the TME and explore how these microbial metabolites can be harnessed in clinical settings to develop more effective cancer treatments. These studies should specifically investigate the combined impact of microbial metabolites with current treatments. Furthermore, it is necessary to investigate the synthesis and modification of microbial metabolites to optimize their effectiveness and guarantee their safety. These studies will therefore extensively investigate the potential of microbial metabolites as supplementary therapeutic agents and present new opportunities for cancer treatment.

Availability of data and materials

Not applicable.

Authors' contributions

YZ, WH, YF and YW performed the literature review and wrote the manuscript. YZ and JX revised the figures and tables. YZ, WH and JX revised the manuscript. YZ, WH, TS and JX were involved in the conception of the study. All authors have read and approved the final version of the manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.


Not applicable.


This work was supported by National Nature Science Foundation of China (grant no. 82373113), Shenyang Breast Cancer Clinical Medical Research Center (grant no. 2020-48-3-1), LiaoNing Revitalization Talents Program (grant no. XLYC1907160), Beijing Medical Award Foundation (grant no. YXJL-2020-0941-0752), Wu Jieping Medical Foundation (grant no. 320.6750.2020-12-21, 320.6750.2020-6-30) and The Fundamental Research Funds for the Central Universities (grant nos. 202229 and 202230).



Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I and Jemal A: Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 74:229–263. 2024. View Article : Google Scholar : PubMed/NCBI


Damelin M, Bankovich A, Bernstein J, Lucas J, Chen L, Williams S, Park A, Aguilar J, Ernstoff E, Charati M, et al: A PTK7-targeted antibody-drug conjugate reduces tumor-initiating cells and induces sustained tumor regressions. Sci Transl Med. 9:eaag26112017. View Article : Google Scholar : PubMed/NCBI


Kamada T, Togashi Y, Tay C, Ha D, Sasaki A, Nakamura Y, Sato E, Fukuoka S, Tada Y, Tanaka A, et al: PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc Natl Acad Sci USA. 116:9999–10008. 2019. View Article : Google Scholar :


Srivastava S, Furlan SN, Jaeger-Ruckstuhl CA, Sarvothama M, Berger C, Smythe KS, Garrison SM, Specht JM, Lee SM, Amezquita RA, et al: Immunogenic chemotherapy enhances recruitment of CAR-T cells to lung tumors and improves antitumor efficacy when combined with checkpoint blockade. Cancer Cell. 39:193–208.e10. 2021. View Article : Google Scholar


Zhao Y, Li ZX, Zhu YJ, Fu J, Zhao XF, Zhang YN, Wang S, Wu JM, Wang KT, Wu R, et al: Single-Cell transcriptome analysis uncovers intratumoral heterogeneity and underlying mechanisms for drug resistance in hepatobiliary tumor organoids. Adv Sci (Weinh). 8:e20038972021. View Article : Google Scholar : PubMed/NCBI


He X, Smith SE, Chen S, Li H, Wu D, Meneses-Giles PI, Wang Y, Hembree M, Yi K, Zhao X, et al: Tumor-initiating stem cell shapes its microenvironment into an immunosuppressive barrier and pro-tumorigenic niche. Cell Rep. 36:1096742021. View Article : Google Scholar : PubMed/NCBI


Lam KC, Araya RE, Huang A, Chen Q, Di Modica M, Rodrigues RR, Lopès A, Johnson SB, Schwarz B, Bohrnsen E, et al: Microbiota triggers STING-type I IFN-dependent monocyte reprogramming of the tumor microenvironment. Cell. 184:5338–5356.e21. 2021. View Article : Google Scholar : PubMed/NCBI


Routy B, Lenehan JG, Miller WH Jr, Jamal R, Messaoudene M, Daisley BA, Hes C, Al KF, Martinez-Gili L, Punčochář M, et al: Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: A phase I trial. Nat Med. 29:2121–2132. 2023. View Article : Google Scholar : PubMed/NCBI


Schneider KM, Mohs A, Gui W, Galvez EJC, Candels LS, Hoenicke L, Muthukumarasamy U, Holland CH, Elfers C, Kilic K, et al: Imbalanced gut microbiota fuels hepatocellular carcinoma development by shaping the hepatic inflammatory microenvironment. Nat Commun. 13:39642022. View Article : Google Scholar : PubMed/NCBI


Peng R, Liu S, You W, Huang Y, Hu C, Gao Y, Jia X, Li G, Xu Z and Chen Y: Gastric microbiome alterations are associated with decreased CD8+ Tissue-Resident Memory T cells in the tumor microenvironment of gastric cancer. Cancer Immunol Res. 10:1224–1240. 2022. View Article : Google Scholar : PubMed/NCBI


Zhu Y, Shi T, Lu X, Xu Z, Qu J, Zhang Z, Shi G, Shen S, Hou Y, Chen Y and Wang T: Fungal-induced glycolysis in macrophages promotes colon cancer by enhancing innate lymphoid cell secretion of IL-22. EMBO J. 40:e1053202021. View Article : Google Scholar : PubMed/NCBI


Protopsaltis NJ, Liang W, Nudleman E and Ferrara N: Interleukin-22 promotes tumor angiogenesis. Angiogenesis. 22:311–323. 2019. View Article : Google Scholar


Briukhovetska D, Suarez-Gosalvez J, Voigt C, Markota A, Giannou AD, Schübel M, Jobst J, Zhang T, Dörr J, Märkl F, et al: T cell-derived interleukin-22 drives the expression of CD155 by cancer cells to suppress NK cell function and promote metastasis. Immunity. 56:143–161.e11. 2023. View Article : Google Scholar : PubMed/NCBI


Chen C, Song X, Wei W, Zhong H, Dai J, Lan Z, Li F, Yu X, Feng Q, Wang Z, et al: The microbiota continuum along the female reproductive tract and its relation to uterine-related diseases. Nat Commun. 8:8752017. View Article : Google Scholar : PubMed/NCBI


Flemer B, Warren RD, Barrett MP, Cisek K, Das A, Jeffery IB, Hurley E, O'Riordain M, Shanahan F and O'Toole PW: The oral microbiota in colorectal cancer is distinctive and predictive. Gut. 67:1454–1463. 2018. View Article : Google Scholar


Soto-Pantoja DR, Gaber M, Arnone AA, Bronson SM, Cruz-Diaz N, Wilson AS, Clear KYJ, Ramirez MU, Kucera GL, Levine EA, et al: Diet alters entero-mammary signaling to regulate the breast microbiome and tumorigenesis. Cancer Res. 81:3890–3904. 2021. View Article : Google Scholar : PubMed/NCBI


O'Dwyer DN, Ashley SL, Gurczynski SJ, Xia M, Wilke C, Falkowski NR, Norman KC, Arnold KB, Huffnagle GB, Salisbury ML, et al: Lung microbiota contribute to pulmonary inflammation and disease progression in pulmonary fibrosis. Am J Respir Crit Care Med. 199:1127–1138. 2019. View Article : Google Scholar : PubMed/NCBI


Sipos A, Ujlaki G, Mikó E, Maka E, Szabó J, Uray K, Krasznai Z and Bai P: The role of the microbiome in ovarian cancer: Mechanistic insights into oncobiosis and to bacterial metabolite signaling. Mol Med. 27:332021. View Article : Google Scholar : PubMed/NCBI


Ma C, Han M, Heinrich B, Fu Q, Zhang Q, Sandhu M, Agdashian D, Terabe M, Berzofsky JA, Fako V, et al: Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science. 360:eaan59312018. View Article : Google Scholar : PubMed/NCBI


Imai S, Ooki T, Murata-Kamiya N, Komura D, Tahmina K, Wu W, Takahashi-Kanemitsu A, Knight CT, Kunita A, Suzuki N, et al: Helicobacter pylori CagA elicits BRCAness to induce genome instability that may underlie bacterial gastric carcinogenesis. Cell Host Microbe. 29:941–958.e10. 2021. View Article : Google Scholar : PubMed/NCBI


Bell HN, Rebernick RJ, Goyert J, Singhal R, Kuljanin M, Kerk SA, Huang W, Das NK, Andren A, Solanki S, et al: Reuterin in the healthy gut microbiome suppresses colorectal cancer growth through altering redox balance. Cancer Cell. 40:185–200.e6. 2022. View Article : Google Scholar :


Zhu X, Li K, Liu G, Wu R, Zhang Y, Wang S, Xu M, Lu L and Li P: Microbial metabolite butyrate promotes anti-PD-1 antitumor efficacy by modulating T cell receptor signaling of cytotoxic CD8 T cell. Gut Microbes. 15:22491432023. View Article : Google Scholar : PubMed/NCBI


Jiang SS, Xie YL, Xiao XY, Kang ZR, Lin XL, Zhang L, Li CS, Qian Y, Xu PP, Leng XX, et al: Fusobacterium nucleatum-derived succinic acid induces tumor resistance to immunotherapy in colorectal cancer. Cell Host Microbe. 31:781–797.e9. 2023. View Article : Google Scholar : PubMed/NCBI


Behary J, Amorim N, Jiang XT, Raposo A, Gong L, McGovern E, Ibrahim R, Chu F, Stephens C, Jebeili H, et al: Gut microbiota impact on the peripheral immune response in non-alcoholic fatty liver disease related hepatocellular carcinoma. Nat Commun. 12:1872021. View Article : Google Scholar : PubMed/NCBI


Høgh RI, Møller SH, Jepsen SD, Mellergaard M, Lund A, Pejtersen M, Fitzner E, Andresen L and Skov S: Metabolism of short-chain fatty acid propionate induces surface expression of NKG2D ligands on cancer cells. FASEB J. 34:15531–15546. 2020. View Article : Google Scholar : PubMed/NCBI


Sun K, Xu R, Ma F, Yang N, Li Y, Sun X, Jin P, Kang W, Jia L, Xiong J, et al: scRNA-seq of gastric tumor shows complex intercellular interaction with an alternative T cell exhaustion trajectory. Nat Commun. 13:49432022. View Article : Google Scholar : PubMed/NCBI


Leader AM, Grout JA, Maier BB, Nabet BY, Park MD, Tabachnikova A, Chang C, Walker L, Lansky A, Le Berichel J, et al: Single-cell analysis of human non-small cell lung cancer lesions refines tumor classification and patient stratification. Cancer Cell. 39:1594–1609.e12. 2021. View Article : Google Scholar : PubMed/NCBI


Huang J, Lee HY, Zhao X, Han J, Su Y, Sun Q, Shao J, Ge J, Zhao Y, Bai X, et al: Interleukin-17D regulates group 3 innate lymphoid cell function through its receptor CD93. Immunity. 54:673–686.e4. 2021. View Article : Google Scholar : PubMed/NCBI


Wu L, Jin Y, Zhao X, Tang K, Zhao Y, Tong L, Yu X, Xiong K, Luo C, Zhu J, et al: Tumor aerobic glycolysis confers immune evasion through modulating sensitivity to T cell-mediated bystander killing via TNF-α. Cell Metab. 35:1580–1596.e9. 2023. View Article : Google Scholar


Brown TP and Ganapathy V: Lactate/GPR81 signaling and proton motive force in cancer: Role in angiogenesis, immune escape, nutrition, and Warburg phenomenon. Pharmacol Ther. 206:1074512020. View Article : Google Scholar


Tang T, Huang X, Lu M, Zhang G, Han X and Liang T: Transcriptional control of pancreatic cancer immunosuppression by metabolic enzyme CD73 in a tumor-autonomous and -autocrine manner. Nat Commun. 14:33642023. View Article : Google Scholar : PubMed/NCBI


Bell HN, Huber AK, Singhal R, Korimerla N, Rebernick RJ, Kumar R, El-Derany MO, Sajjakulnukit P, Das NK, Kerk SA, et al: Microenvironmental ammonia enhances T cell exhaustion in colorectal cancer. Cell Metab. 35:134–149.e6. 2023. View Article : Google Scholar :


Shi Q, Wang J, Zhou M, Zheng R, Zhang X and Liu B: Gut Lactobacillus contribute to the progression of breast cancer by affecting the antitumor activities of immune cells in the TME of tumor-bearing mice. Int Immunopharmacol. 124(Pt B): 1110392023. View Article : Google Scholar : PubMed/NCBI


Nejman D, Livyatan I, Fuks G, Gavert N, Zwang Y, Geller LT, Rotter-Maskowitz A, Weiser R, Mallel G, Gigi E, et al: The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science. 368:973–980. 2020. View Article : Google Scholar : PubMed/NCBI


Song W, Tiruthani K, Wang Y, Shen L, Hu M, Dorosheva O, Qiu K, Kinghorn KA, Liu R and Huang L: Trapping of lipopolysaccharide to promote immunotherapy against colorectal cancer and attenuate liver metastasis. Adv Mater. 30:e18050072018. View Article : Google Scholar : PubMed/NCBI


Liu CH, Chen Z, Chen K, Liao FT, Chung CE, Liu X, Lin YC, Keohavong P, Leikauf GD and Di YP: Lipopolysaccharide-Mediated chronic inflammation promotes tobacco carcinogen-induced lung cancer and determines the efficacy of immunotherapy. Cancer Res. 81:144–157. 2021. View Article : Google Scholar :


Zhong W, Wu K, Long Z, Zhou X, Zhong C, Wang S, Lai H, Guo Y, Lv D, Lu J and Mao X: Gut dysbiosis promotes prostate cancer progression and docetaxel resistance via activating NF-κB-IL6-STAT3 axis. Microbiome. 10:942022. View Article : Google Scholar


Zhu G, Huang Q, Huang Y, Zheng W, Hua J, Yang S, Zhuang J, Wang J and Ye J: Lipopolysaccharide increases the release of VEGF-C that enhances cell motility and promotes lymphangiogenesis and lymphatic metastasis through the TLR4-NF-κB/JNK pathways in colorectal cancer. Oncotarget. 7:73711–73724. 2016. View Article : Google Scholar : PubMed/NCBI


Liu C, Yao Z, Wang J, Zhang W, Yang Y, Zhang Y, Qu X, Zhu Y, Zou J, Peng S, et al: Macrophage-derived CCL5 facilitates immune escape of colorectal cancer cells via the p65/STAT3-CSN5-PD-L1 pathway. Cell Death Differ. 27:1765–1781. 2020. View Article : Google Scholar :


Feitelson MA, Arzumanyan A, Medhat A and Spector I: Short-chain fatty acids in cancer pathogenesis. Cancer Metastasis Rev. 42:677–698. 2023. View Article : Google Scholar : PubMed/NCBI


Brennan CA, Clay SL, Lavoie SL, Bae S, Lang JK, Fonseca-Pereira D, Rosinski KG, Ou N, Glickman JN and Garrett WS: Fusobacterium nucleatum drives a pro-inflammatory intestinal microenvironment through metabolite receptor-dependent modulation of IL-17 expression. Gut Microbes. 13:19877802021. View Article : Google Scholar : PubMed/NCBI


Matsushita M, Fujita K, Hayashi T, Kayama H, Motooka D, Hase H, Jingushi K, Yamamichi G, Yumiba S, Tomiyama E, et al: Gut microbiota-derived short-chain fatty acids promote prostate cancer growth via IGF1 signaling. Cancer Res. 81:4014–4026. 2021. View Article : Google Scholar : PubMed/NCBI


Meiser J, Schuster A, Pietzke M, Vande Voorde J, Athineos D, Oizel K, Burgos-Barragan G, Wit N, Dhayade S, Morton JP, et al: Increased formate overflow is a hallmark of oxidative cancer. Nat Commun. 9:13682018. View Article : Google Scholar : PubMed/NCBI


Hennequart M, Pilley SE, Labuschagne CF, Coomes J, Mervant L, Driscoll PC, Legrave NM, Lee Y, Kreuzaler P, Macintyre B, et al: ALDH1L2 regulation of formate, formyl-methionine, and ROS controls cancer cell migration and metastasis. Cell Rep. 42:1125622023. View Article : Google Scholar : PubMed/NCBI


Ternes D, Tsenkova M, Pozdeev VI, Meyers M, Koncina E, Atatri S, Schmitz M, Karta J, Schmoetten M, Heinken A, et al: The gut microbial metabolite formate exacerbates colorectal cancer progression. Nat Metab. 4:458–475. 2022. View Article : Google Scholar : PubMed/NCBI


Kim M, Vogtmann E, Ahlquist DA, Devens ME, Kisiel JB, Taylor WR, White BA, Hale VL, Sung J, Chia N, et al: Fecal metabolomic signatures in colorectal adenoma patients are associated with gut microbiota and early events of colorectal cancer pathogenesis. mBio. 11:e03186–19. 2020. View Article : Google Scholar : PubMed/NCBI


Petrick JL, Florio AA, Koshiol J, Pfeiffer RM, Yang B, Yu K, Chen CJ, Yang HI, Lee MH and McGlynn KA: Prediagnostic concentrations of circulating bile acids and hepatocellular carcinoma risk: REVEAL-HBV and HCV studies. Int J Cancer. 147:2743–2753. 2020. View Article : Google Scholar : PubMed/NCBI


Funabashi M, Grove TL, Wang M, Varma Y, McFadden ME, Brown LC, Guo C, Higginbottom S, Almo SC and Fischbach MA: A metabolic pathway for bile acid dehydroxylation by the gut microbiome. Nature. 582:566–570. 2020. View Article : Google Scholar : PubMed/NCBI


Sun L, Zhang Y, Cai J, Rimal B, Rocha ER, Coleman JP, Zhang C, Nichols RG, Luo Y, Kim B, et al: Bile salt hydrolase in non-enterotoxigenic Bacteroides potentiates colorectal cancer. Nat Commun. 14:7552023. View Article : Google Scholar : PubMed/NCBI


Song X, An Y, Chen D, Zhang W, Wu X, Li C, Wang S, Dong W, Wang B, Liu T, et al: Microbial metabolite deoxycholic acid promotes vasculogenic mimicry formation in intestinal carcinogenesis. Cancer Sci. 113:459–477. 2022. View Article : Google Scholar :


Nguyen TT, Lian S, Ung TT, Xia Y, Han JY and Jung YD: Lithocholic acid stimulates IL-8 expression in human colorectal cancer cells via activation of Erk1/2 MAPK and suppression of STAT3 activity. J Cell Biochem. 118:2958–2967. 2017. View Article : Google Scholar : PubMed/NCBI


Lee YS, Choi I, Ning Y, Kim NY, Khatchadourian V, Yang D, Chung HK, Choi D, LaBonte MJ, Ladner RD, et al: Interleukin-8 and its receptor CXCR2 in the tumour microenvironment promote colon cancer growth, progression and metastasis. Br J Cancer. 106:1833–1841. 2012. View Article : Google Scholar : PubMed/NCBI


Fang ZZ, Zhang D, Cao YF, Xie C, Lu D, Sun DX, Tanaka N, Jiang C, Chen Q, Chen Y, et al: Irinotecan (CPT-11)-induced elevation of bile acids potentiates suppression of IL-10 expression. Toxicol Appl Pharmacol. 291:21–27. 2016. View Article : Google Scholar :


Liu Q, Yang C, Wang S, Shi D, Wei C, Song J, Lin X, Dou R, Bai J, Xiang Z, et al: Wnt5a-induced M2 polarization of tumor-associated macrophages via IL-10 promotes colorectal cancer progression. Cell Commun Signal. 18:512020. View Article : Google Scholar : PubMed/NCBI


Hang S, Paik D, Yao L, Kim E, Trinath J, Lu J, Ha S, Nelson BN, Kelly SP, Wu L, et al: Bile acid metabolites control TH17 and Treg cell differentiation. Nature. 576:143–148. 2019. View Article : Google Scholar : PubMed/NCBI


Wang N, Yang J, Han W, Han M, Liu X, Jiang L, Cao H, Jing M, Sun T and Xu J: Identifying distinctive tissue and fecal microbial signatures and the tumor-promoting effects of deoxycholic acid on breast cancer. Front Cell Infect Microbiol. 12:10299052022. View Article : Google Scholar : PubMed/NCBI


Riquelme E, Zhang Y, Zhang L, Montiel M, Zoltan M, Dong W, Quesada P, Sahin I, Chandra V, San Lucas A, et al: Tumor microbiome diversity and composition influence pancreatic cancer outcomes. Cell. 178:795–806.e12. 2019. View Article : Google Scholar : PubMed/NCBI


Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, et al: Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 359:97–103. 2018. View Article : Google Scholar


Huang J, Zheng X, Kang W, Hao H, Mao Y, Zhang H, Chen Y, Tan Y, He Y, Zhao W and Yin Y: Metagenomic and metabolomic analyses reveal synergistic effects of fecal microbiota transplantation and anti-PD-1 therapy on treating colorectal cancer. Front Immunol. 13:8749222022. View Article : Google Scholar : PubMed/NCBI


Davar D, Dzutsev AK, McCulloch JA, Rodrigues RR, Chauvin JM, Morrison RM, Deblasio RN, Menna C, Ding Q, Pagliano O, et al: Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science. 371:595–602. 2021. View Article : Google Scholar : PubMed/NCBI


Joachim L, Göttert S, Sax A, Steiger K, Neuhaus K, Heinrich P, Fan K, Orberg ET, Kleigrewe K, Ruland J, et al: The microbial metabolite desaminotyrosine enhances T-cell priming and cancer immunotherapy with immune checkpoint inhibitors. EBioMedicine. 97:1048342023. View Article : Google Scholar : PubMed/NCBI


Green BL, Myojin Y, Ma C, Ruf B, Ma L, Zhang Q, Rosato U, Qi J, Revsine M, Wabitsch S and Bauer K: Immunosuppressive CD29+ Treg accumulation in the liver in mice on checkpoint inhibitor therapy. Gut. 73:509–520. 2024.


Klement JD, Paschall AV, Redd PS, Ibrahim ML, Lu C, Yang D, Celis E, Abrams SI, Ozato K and Liu K: An osteopontin/CD44 immune checkpoint controls CD8+ T cell activation and tumor immune evasion. J Clin Invest. 128:5549–5560. 2018. View Article : Google Scholar : PubMed/NCBI


Thomas MS and Fernandez ML: Trimethylamine N-Oxide (TMAO), diet and cardiovascular disease. Curr Atheroscler Rep. 23:122021. View Article : Google Scholar : PubMed/NCBI


Wu Y, Rong X, Pan M, Wang T, Yang H, Chen X, Xiao Z and Zhao C: Integrated analysis reveals the gut microbial metabolite TMAO promotes inflammatory hepatocellular carcinoma by upregulating POSTN. Front Cell Dev Biol. 10:8401712022. View Article : Google Scholar : PubMed/NCBI


Mirji G, Worth A, Bhat SA, El Sayed M, Kannan T, Goldman AR, Tang HY, Liu Q, Auslander N, Dang CV, et al: The microbiome-derived metabolite TMAO drives immune activation and boosts responses to immune checkpoint blockade in pancreatic cancer. Sci Immunol. 7:eabn07042022. View Article : Google Scholar : PubMed/NCBI


Jalandra R, Dalal N, Yadav AK, Verma D, Sharma M, Singh R, Khosla A, Kumar A and Solanki PR: Emerging role of trimethylamine-N-oxide (TMAO) in colorectal cancer. Appl Microbiol Biotechnol. 105:7651–7660. 2021. View Article : Google Scholar : PubMed/NCBI


Luo Z, Yu X, Wang C, Zhao H, Wang X and Guan X: Trimethylamine N-oxide promotes oxidative stress and lipid accumulation in macrophage foam cells via the Nrf2/ABCA1 pathway. J Physiol Biochem. 80:67–79. 2024. View Article : Google Scholar


Baldominos P, Barbera-Mourelle A, Barreiro O, Huang Y, Wight A, Cho JW, Zhao X, Estivill G, Adam I, Sanchez X, et al: Quiescent cancer cells resist T cell attack by forming an immunosuppressive niche. Cell. 185:1694–1708.e19. 2022. View Article : Google Scholar


Wang H, Rong X, Zhao G, Zhou Y, Xiao Y, Ma D, Jin X, Wu Y, Yan Y, Yang H, et al: The microbial metabolite trimethylamine N-oxide promotes antitumor immunity in triple-negative breast cancer. Cell Metab. 34:581–594.e8. 2022. View Article : Google Scholar : PubMed/NCBI


Yang S, Dai H, Lu Y, Li R, Gao C and Pan S: Trimethylamine N-Oxide promotes cell proliferation and angiogenesis in colorectal cancer. J Immunol Res. 2022:70438562022. View Article : Google Scholar : PubMed/NCBI


Roberts AB, Gu X, Buffa JA, Hurd AG, Wang Z, Zhu W, Gupta N, Skye SM, Cody DB, Levison BS, et al: Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential. Nat Med. 24:1407–1417. 2018. View Article : Google Scholar : PubMed/NCBI


Zhu W, Gregory JC, Org E, Buffa JA, Gupta N, Wang Z, Li L, Fu X, Wu Y, Mehrabian M, et al: Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell. 165:111–124. 2016. View Article : Google Scholar : PubMed/NCBI


Li Z, Wu Z, Yan J, Liu H, Liu Q, Deng Y, Ou C and Chen M: Gut microbe-derived metabolite trimethylamine N-oxide induces cardiac hypertrophy and fibrosis. Lab Invest. 99:346–357. 2019. View Article : Google Scholar


Peng L, Li ZR, Green RS, Holzman IR and Lin J: Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. J Nutr. 139:1619–1625. 2009. View Article : Google Scholar : PubMed/NCBI


Zhang SL, Mao YQ, Zhang ZY, Li ZM, Kong CY, Chen HL, Cai PR, Han B, Ye T and Wang LS: Pectin supplement significantly enhanced the anti-PD-1 efficacy in tumor-bearing mice humanized with gut microbiota from patients with colorectal cancer. Theranostics. 11:4155–4170. 2021. View Article : Google Scholar : PubMed/NCBI


Yao Y, Cai X, Fei W, Ye Y, Zhao M and Zheng C: The role of short-chain fatty acids in immunity, inflammation and metabolism. Crit Rev Food Sci Nutr. 62:1–12. 2022. View Article : Google Scholar


Song Q, Zhang X, Liu W, Wei H, Liang W, Zhou Y, Ding Y, Ji F, Ho-Kwan Cheung A, Wong N and Yu J: Bifidobacterium pseudolongum-generated acetate suppresses non-alcoholic fatty liver disease-associated hepatocellular carcinoma. J Hepatol. 79:1352–1365. 2023. View Article : Google Scholar : PubMed/NCBI


Bindels LB, Porporato P, Dewulf EM, Verrax J, Neyrinck AM, Martin JC, Scott KP, Buc Calderon P, Feron O, Muccioli GG, et al: Gut microbiota-derived propionate reduces cancer cell proliferation in the liver. Br J Cancer. 107:1337–1344. 2012. View Article : Google Scholar : PubMed/NCBI


Thirunavukkarasan M, Wang C, Rao A, Hind T, Teo YR, Siddiquee AA, Goghari MAI, Kumar AP and Herr DR: Short-chain fatty acid receptors inhibit invasive phenotypes in breast cancer cells. PLoS One. 12:e01863342017. View Article : Google Scholar : PubMed/NCBI


Singh N, Gurav A, Sivaprakasam S, Brady E, Padia R, Shi H, Thangaraju M, Prasad PD, Manicassamy S, Munn DH, et al: Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity. 40:128–139. 2014. View Article : Google Scholar : PubMed/NCBI


Lavoie S, Chun E, Bae S, Brennan CA, Gallini Comeau CA, Lang JK, Michaud M, Hoveyda HR, Fraser GL, Fuller MH, et al: Expression of free fatty acid receptor 2 by dendritic cells prevents their expression of interleukin 27 and is required for maintenance of mucosal barrier and immune response against colorectal tumors in mice. Gastroenterology. 158:1359–1372.e9. 2020. View Article : Google Scholar : PubMed/NCBI


Ramaiah MJ, Tangutur AD and Manyam RR: Epigenetic modulation and understanding of HDAC inhibitors in cancer therapy. Life Sci. 277:1195042021. View Article : Google Scholar : PubMed/NCBI


Shanmugam G, Rakshit S and Sarkar K: HDAC inhibitors: Targets for tumor therapy, immune modulation and lung diseases. Transl Oncol. 16:1013122022. View Article : Google Scholar


Li X, Su X, Liu R, Pan Y, Fang J, Cao L, Feng C, Shang Q, Chen Y, Shao C and Shi Y: HDAC inhibition potentiates antitumor activity of macrophages and enhances anti-PD-L1-mediated tumor suppression. Oncogene. 40:1836–1850. 2021. View Article : Google Scholar : PubMed/NCBI


Luu M, Riester Z, Baldrich A, Reichardt N, Yuille S, Busetti A, Klein M, Wempe A, Leister H, Raifer H, et al: Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer. Nat Commun. 12:40772021. View Article : Google Scholar :


Dupraz L, Magniez A, Rolhion N, Richard ML, Da Costa G, Touch S, Mayeur C, Planchais J, Agus A, Danne C, et al: Gut microbiota-derived short-chain fatty acids regulate IL-17 production by mouse and human intestinal γδ T cells. Cell Rep. 36:1093322021. View Article : Google Scholar


Zhang H, Du M, Yang Q and Zhu MJ: Butyrate suppresses murine mast cell proliferation and cytokine production through inhibiting histone deacetylase. J Nutr Biochem. 27:299–306. 2016. View Article : Google Scholar


Qiao P, Zhang C, Yu J, Shao S, Zhang J, Fang H, Chen J, Luo Y, Zhi D, Li Q, et al: Quinolinic acid, a tryptophan metabolite of the skin microbiota, negatively regulates NLRP3 inflammasome through AhR in psoriasis. J Invest Dermatol. 142:2184–2193.e6. 2022. View Article : Google Scholar : PubMed/NCBI


Fang Z, Pan T, Li L, Wang H, Zhu J, Zhang H, Zhao J, Chen W and Lu W: Bifidobacterium longum mediated tryptophan metabolism to improve atopic dermatitis via the gut-skin axis. Gut Microbes. 14:20447232022. View Article : Google Scholar : PubMed/NCBI


Sehgal R, Ilha M, Vaittinen M, Kaminska D, Männistö V, Kärjä V, Tuomainen M, Hanhineva K, Romeo S, Pajukanta P, et al: Indole-3-Propionic acid, a Gut-Derived tryptophan metabolite, associates with hepatic fibrosis. Nutrients. 13:35092021. View Article : Google Scholar : PubMed/NCBI


Cheng Y, Jin UH, Allred CD, Jayaraman A, Chapkin RS and Safe S: Aryl hydrocarbon receptor activity of tryptophan metabolites in young adult mouse colonocytes. Drug Metab Dispos. 43:1536–1543. 2015. View Article : Google Scholar : PubMed/NCBI


Bender MJ, McPherson AC, Phelps CM, Pandey SP, Laughlin CR, Shapira JH, Medina Sanchez L, Rana M, Richie TG, Mims TS, et al: Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment. Cell. 186:1846–1862.e26. 2023. View Article : Google Scholar : PubMed/NCBI


Hezaveh K, Shinde RS, Klötgen A, Halaby MJ, Lamorte S, Ciudad MT, Quevedo R, Neufeld L, Liu ZQ, Jin R, et al: Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress antitumor immunity. Immunity. 55:324–340.e8. 2022. View Article : Google Scholar


Zhang Q, Zhao Q, Li T, Lu L, Wang F, Zhang H, Liu Z, Ma H, Zhu Q, Wang J, et al: Lactobacillus plantarum-derived indole-3-lactic acid ameliorates colorectal tumorigenesis via epigenetic regulation of CD8+ T cell immunity. Cell Metab. 35:943–960.e9. 2023. View Article : Google Scholar


Garris CS, Arlauckas SP, Kohler RH, Trefny MP, Garren S, Piot C, Engblom C, Pfirschke C, Siwicki M, Gungabeesoon J, et al: Successful Anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12. Immunity. 49:1148–1161.e7. 2018. View Article : Google Scholar


Sári Z, Mikó E, Kovács T, Boratkó A, Ujlaki G, Jankó L, Kiss B, Uray K and Bai P: Indoxylsulfate, a metabolite of the microbiome, has cytostatic effects in breast cancer via activation of AHR and PXR receptors and induction of oxidative stress. Cancers (Basel). 12:29152020. View Article : Google Scholar : PubMed/NCBI


Sharma MD, Pacholczyk R, Shi H, Berrong ZJ, Zakharia Y, Greco A, Chang CS, Eathiraj S, Kennedy E, Cash T, et al: Inhibition of the BTK-IDO-mTOR axis promotes differentiation of monocyte-lineage dendritic cells and enhances antitumor T cell immunity. Immunity. 54:2354–2371.e8. 2021. View Article : Google Scholar


Campesato LF, Budhu S, Tchaicha J, Weng CH, Gigoux M, Cohen IJ, Redmond D, Mangarin L, Pourpe S, Liu C, et al: Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine. Nat Commun. 11:40112020. View Article : Google Scholar : PubMed/NCBI


Liu H, Xu X, Wang J, Wang W, Ma C, Sun T and Shao Q: Clinical study on different doses and fractionated radiotherapies for multiple brain metastases of non-EGFR mutant lung adenocarcinoma. Ann Palliat Med. 9:2003–2012. 2020. View Article : Google Scholar : PubMed/NCBI


Liu Z, Huang L, Wang H, Shi Z, Huang Y, Liang L, Wang R and Hu K: Predicting nomogram for severe oral mucositis in patients with nasopharyngeal carcinoma during intensity-modulated radiation therapy: A retrospective cohort study. Curr Oncol. 30:219–232. 2022. View Article : Google Scholar


Guo H, Chou WC, Lai Y, Liang K, Tam JW, Brickey WJ, Chen L, Montgomery ND, Li X, Bohannon LM, et al: Multi-omics analyses of radiation survivors identify radioprotective microbes and metabolites. Science. 370:eaay90972020. View Article : Google Scholar : PubMed/NCBI


Zhang Y, Yan T, Mo W, Song B, Zhang Y, Geng F, Hu Z, Yu D and Zhang S: Altered bile acid metabolism in skin tissues in response to ionizing radiation: deoxycholic acid (DCA) as a novel treatment for radiogenic skin injury. Int J Radiat Biol. 100:87–98. 2024. View Article : Google Scholar


Han JX, Tao ZH, Wang JL, Zhang L, Yu CY, Kang ZR, Xie Y, Li J, Lu S, Cui Y, et al: Microbiota-derived tryptophan catabolites mediate the chemopreventive effects of statins on colorectal cancer. Nat Microbiol. 8:919–933. 2023. View Article : Google Scholar : PubMed/NCBI


Deng B, Yang B, Chen J, Wang S, Zhang W, Guo Y, Han Y, Li H, Dang Y, Yuan Y, et al: Gallic acid induces T-helper-1-like Treg cells and strengthens immune checkpoint blockade efficacy. J Immunother Cancer. 10:e0040372022. View Article : Google Scholar :


Li K, Xiao Y, Bian J, Han L, He C, El-Omar E, Gong L and Wang M: Ameliorative effects of gut microbial metabolite urolithin a on pancreatic diseases. Nutrients. 14:25492022. View Article : Google Scholar : PubMed/NCBI


González-Sarrías A, Miguel V, Merino G, Lucas R, Morales JC, Tomás-Barberán F, Alvarez AI and Espín JC: The gut microbiota ellagic acid-derived metabolite urolithin A and its sulfate conjugate are substrates for the drug efflux transporter breast cancer resistance protein (ABCG2/BCRP). J Agric Food Chem. 61:4352–4359. 2013. View Article : Google Scholar : PubMed/NCBI


Ghosh S, Singh R, Vanwinkle ZM, Guo H, Vemula PK, Goel A, Haribabu B and Jala VR: Microbial metabolite restricts 5-fluorouracil-resistant colonic tumor progression by sensitizing drug transporters via regulation of FOXO3-FOXM1 axis. Theranostics. 12:5574–5595. 2022. View Article : Google Scholar : PubMed/NCBI


Zhang Y, Jiang L, Su P, Yu T, Ma Z, Liu Y and Yu J: Urolithin A suppresses tumor progression and induces autophagy in gastric cancer via the PI3K/Akt/mTOR pathway. Drug Dev Res. 84:172–184. 2023. View Article : Google Scholar


Blouin JM, Penot G, Collinet M, Nacfer M, Forest C, Laurent-Puig P, Coumoul X, Barouki R, Benelli C and Bortoli S: Butyrate elicits a metabolic switch in human colon cancer cells by targeting the pyruvate dehydrogenase complex. Int J Cancer. 128:2591–2601. 2011. View Article : Google Scholar


Yuksel B, Deveci Ozkan A, Aydın D and Betts Z: Evaluation of the antioxidative and genotoxic effects of sodium butyrate on breast cancer cells. Saudi J Biol Sci. 29:1394–1401. 2022. View Article : Google Scholar : PubMed/NCBI


Zhao ZH, Wang ZX, Zhou D, Han Y, Ma F, Hu Z, Xin FZ, Liu XL, Ren TY, Zhang F, et al: Sodium butyrate supplementation inhibits hepatic steatosis by stimulating liver kinase B1 and insulin-induced gene. Cell Mol Gastroenterol Hepatol. 12:857–871. 2021. View Article : Google Scholar : PubMed/NCBI


Encarnação JC, Pires AS, Amaral RA, Gonçalves TJ, Laranjo M, Casalta-Lopes JE, Gonçalves AC, Sarmento-Ribeiro AB, Abrantes AM and Botelho MF: Butyrate, a dietary fiber derivative that improves irinotecan effect in colon cancer cells. J Nutr Biochem. 56:183–192. 2018. View Article : Google Scholar : PubMed/NCBI


Shuwen H, Yangyanqiu W, Jian C, Boyang H, Gong C and Jing Z: Synergistic effect of sodium butyrate and oxaliplatin on colorectal cancer. Transl Oncol. 27:1015982023. View Article : Google Scholar


Yu T, Guo F, Yu Y, Sun T, Ma D, Han J, Qian Y, Kryczek I, Sun D, Nagarsheth N, et al: Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. Cell. 170:548–563.e16. 2017. View Article : Google Scholar : PubMed/NCBI


Chen L, Zhao R, Kang Z, Cao Z, Liu N, Shen J, Wang C, Pan F, Zhou X, Liu Z, et al: Delivery of short chain fatty acid butyrate to overcome Fusobacterium nucleatum-induced chemoresistance. J Control Release. 363:43–56. 2023. View Article : Google Scholar : PubMed/NCBI


Tintelnot J, Xu Y, Lesker TR, Schönlein M, Konczalla L, Giannou A D, Pelcza r P, Kylies D, Puelles VG, Bielecka AA, et al: Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer. Nature. 615:168–174. 2023. View Article : Google Scholar : PubMed/NCBI


Colbert LE, El Alam MB, Wang R, Karpinets T, Lo D, Lynn EJ, Harris TA, Elnaggar JH, Yoshida-Court K, Tomasic K, et al: Tumor-resident Lactobacillus iners confer chemoradiation resistance through lactate-induced metabolic rewiring. Cancer Cell. 41:1945–1962.e11. 2023. View Article : Google Scholar : PubMed/NCBI


Chang TK, Yin TC, Su WC, Tsai HL, Huang CW, Chen YC, Li CC, Chen PJ, Ma CJ, Chuang KH, et al: A Pilot Study of Silymarin as Supplementation to reduce toxicities in metastatic colorectal cancer patients treated with first-line FOLFIRI Plus Bevacizumab. Oncol Res. 28:801–809. 2021. View Article : Google Scholar : PubMed/NCBI


Yang W, Chang L, Guo Q, Chen J, Yu W and Zhang W: Programmed cell death protein-1 inhibitors in the treatment of digestive system tumors in Chinese population: An observational study of effectiveness and safety. Ann Palliat Med. 10:9015–9024. 2021. View Article : Google Scholar : PubMed/NCBI


Renga G, Nunzi E, Pariano M, Puccetti M, Bellet MM, Pieraccini G, D'Onofrio F, Santarelli I, Stincardini C, Aversa F, et al: Optimizing therapeutic outcomes of immune checkpoint blockade by a microbial tryptophan metabolite. J Immunother Cancer. 10:e0037252022. View Article : Google Scholar : PubMed/NCBI


Lu C, Liu Z, Klement JD, Yang D, Merting AD, Poschel D, Albers T, Waller JL, Shi H and Liu K: WDR5-H3K4me3 epigenetic axis regulates OPN expression to compensate PD-L1 function to promote pancreatic cancer immune escape. J Immunother Cancer. 9:e0026242021. View Article : Google Scholar : PubMed/NCBI


Wang J, Ge J, Wang Y, Xiong F, Guo J, Jiang X, Zhang L, Deng X, Gong Z, Zhang S, et al: EBV miRNAs BART11 and BART17-3p promote immune escape through the enhancer-mediated transcription of PD-L1. Nat Commun. 13:8662022. View Article : Google Scholar : PubMed/NCBI


Lainé A, Labiad O, Hernandez-Vargas H, This S, Sanlaville A, Léon S, Dalle S, Sheppard D, Travis MA, Paidassi H and Marie JC: Regulatory T cells promote cancer immune-escape through integrin αvβ8-mediated TGF-β activation. Nat Commun. 12:62282021. View Article : Google Scholar


Peng S, Wang R, Zhang X, Ma Y, Zhong L, Li K, Nishiyama A, Arai S, Yano S and Wang W: EGFR-TKI resistance promotes immune escape in lung cancer via increased PD-L1 expression. Mol Cancer. 18:1652019. View Article : Google Scholar : PubMed/NCBI


Mehra S, Garrido VT, Dosch AR, Lamichhane P, Srinivasan S, Singh SP, Zhou Z, De Castro Silva I, Joshi C, Ban Y, et al: Remodeling of stromal immune microenvironment by urolithin a improves survival with immune checkpoint blockade in pancreatic cancer. Cancer Res Commun. 3:1224–1236. 2023. View Article : Google Scholar : PubMed/NCBI


Coutzac C, Jouniaux JM, Paci A, Schmidt J, Mallardo D, Seck A, Asvatourian V, Cassard L, Saulnier P, Lacroix L, et al: Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer. Nat Commun. 11:21682020. View Article : Google Scholar : PubMed/NCBI


Lv B, Wang Y, Ma D, Cheng W, Liu J, Yong T, Chen H and Wang C: Immunotherapy: Reshape the tumor immune microenvironment. Front Immunol. 13:8441422022. View Article : Google Scholar : PubMed/NCBI


Mao X, Xu J, Wang W, Liang C, Hua J, Liu J, Zhang B, Meng Q, Yu X and Shi S: Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives. Mol Cancer. 20:1312021. View Article : Google Scholar : PubMed/NCBI


Korbecki J, Kojder K, Simińska D, Bohatyrewicz R, Gutowska I, Chlubek D and Baranowska-Bosiacka I: CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of the Ligands of Receptors CCR1, CCR2, CCR3, and CCR4. Int J Mol Sci. 21:84122020. View Article : Google Scholar : PubMed/NCBI


Hennessy M, Wahba A, Felix K, Cabrera M, Segura MG, Kundra V, Ravoori MK, Stewart J, Kleinerman ES, Jensen VB, et al: Bempegaldesleukin (BEMPEG; NKTR-214) efficacy as a single agent and in combination with checkpoint-inhibitor therapy in mouse models of osteosarcoma. Int J Cancer. 148:1928–1937. 2021. View Article : Google Scholar


Rosen DB, Kvarnhammar AM, Laufer B, Knappe T, Karlsson JJ, Hong E, Lee YC, Thakar D, Zúñiga LA, Bang K, et al: TransCon IL-2 β/γ: A novel long-acting prodrug with sustained release of an IL-2Rβ/γ-selective IL-2 variant with improved pharmacokinetics and potent activation of cytotoxic immune cells for the treatment of cancer. J Immunother Cancer. 10:e0049912022. View Article : Google Scholar


Naing A, Papadopoulos KP, Autio KA, Ott PA, Patel MR, Wong DJ, Falchook GS, Pant S, Whiteside M, Rasco DR, et al: Safety, antitumor activity, and immune activation of pegylated recombinant human interleukin-10 (AM0010) in patients with advanced solid tumors. J Clin Oncol. 34:3562–3569. 2016. View Article : Google Scholar : PubMed/NCBI


Taniguchi Y, Kurokawa Y, Hagi T, Takahashi T, Miyazaki Y, Tanaka K, Makino T, Yamasaki M, Nakajima K, Mori M and Doki Y: Methylprednisolone inhibits tumor growth and peritoneal seeding induced by surgical stress and post-operative complications. Ann Surg Oncol. 26:2831–2838. 2019. View Article : Google Scholar : PubMed/NCBI


Hailemichael Y, Johnson DH, Abdel-Wahab N, Foo WC, Bentebibel SE, Daher M, Haymaker C, Wani K, Saberian C, Ogata D, et al: Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity. Cancer Cell. 40:509–523.e6. 2022. View Article : Google Scholar : PubMed/NCBI


Xue D, Moon B, Liao J, Guo J, Zou Z, Han Y, Cao S, Wang Y, Fu YX and Peng H: A tumor-specific pro-IL-12 activates preexisting cytotoxic T cells to control established tumors. Sci Immunol. 7:eabi68992022. View Article : Google Scholar : PubMed/NCBI


Agliardi G, Liuzzi AR, Hotblack A, De Feo D, Núñez N, Stowe CL, Friebel E, Nannini F, Rindlisbacher L, Roberts TA, et al: Intratumoral IL-12 delivery empowers CAR-T cell immunotherapy in a pre-clinical model of glioblastoma. Nat Commun. 12:4442021. View Article : Google Scholar : PubMed/NCBI


Chang PV, Hao L, Offermanns S and Medzhitov R: The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci USA. 111:2247–2252. 2014. View Article : Google Scholar : PubMed/NCBI


Mager LF, Burkhard R, Pett N, Cooke NCA, Brown K, Ramay H, Paik S, Stagg J, Groves RA, Gallo M, et al: Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy. Science. 369:1481–1489. 2020. View Article : Google Scholar : PubMed/NCBI


O'Keefe SJ: Diet, microorganisms and their metabolites, and colon cancer. Nat Rev Gastroenterol Hepatol. 13:691–706. 2016. View Article : Google Scholar : PubMed/NCBI


Niekamp P and Kim CH: Microbial metabolite dysbiosis and colorectal cancer. Gut Liver. 17:190–203. 2023. View Article : Google Scholar : PubMed/NCBI


Wu X, Wu Y, He L, Wu L, Wang X and Liu Z: Effects of the intestinal microbial metabolite butyrate on the development of colorectal cancer. J Cancer. 9:2510–2517. 2018. View Article : Google Scholar : PubMed/NCBI


Kaźmierczak-Siedlecka K, Marano L, Merola E, Roviello F and Połom K: Sodium butyrate in both prevention and supportive treatment of colorectal cancer. Front Cell Infect Microbiol. 12:10238062022. View Article : Google Scholar


Zhao H, Wang D, Zhang Z, Xian J and Bai X: Effect of gut microbiota-derived metabolites on immune checkpoint inhibitor therapy: Enemy or friend? Molecules. 27:47992022. View Article : Google Scholar : PubMed/NCBI

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Zhou Y, Han W, Feng Y, Wang Y, Sun T and Xu J: Microbial metabolites affect tumor progression, immunity and therapy prediction by reshaping the tumor microenvironment (Review). Int J Oncol 65: 73, 2024
Zhou, Y., Han, W., Feng, Y., Wang, Y., Sun, T., & Xu, J. (2024). Microbial metabolites affect tumor progression, immunity and therapy prediction by reshaping the tumor microenvironment (Review). International Journal of Oncology, 65, 73.
Zhou, Y., Han, W., Feng, Y., Wang, Y., Sun, T., Xu, J."Microbial metabolites affect tumor progression, immunity and therapy prediction by reshaping the tumor microenvironment (Review)". International Journal of Oncology 65.1 (2024): 73.
Zhou, Y., Han, W., Feng, Y., Wang, Y., Sun, T., Xu, J."Microbial metabolites affect tumor progression, immunity and therapy prediction by reshaping the tumor microenvironment (Review)". International Journal of Oncology 65, no. 1 (2024): 73.