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

Abstract

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.

Keywords: cancer; chemotherapy; gut microbiome; immunotherapy; microbial metabolites; tumor microbiota; tumor microenvironment.

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 BioRender.com. 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.

Figure 2

Various microbial metabolites reshape the TME to promote antitumor immunity. TMAO activates M1 macrophages to release IFN-I. TMAO induces triple-negative breast cancer cell pyroptosis, leading to the release of various tumor-associated antigens into the TME. SCFAs binding to GPR43 expressed on liver cells inhibit the secretion of IL-6. SCFAs binding to GPR109a on macrophages or dendritic cells promote the differentiation of CD4⁺ T cells into Tregs and inhibit differentiation into Th17 cells. SCFAs inhibit the activity of HDACs in tumor cells, thereby promoting the release of INF-γ and TNF-α. I3A binds to the AHR of CD8⁺ T cells, promoting the secretion of IFN-γ. I3LA alters chromatin accessibility, activating CD8⁺ T cells to release IFN-γ. I3LA also binds to dendritic cells to promote the secretion of IL-12. IS induces oxidative stress and nitrosative stress to inhibit EMT. The figure was created using BioRender. com. TME, tumor microenvironment; TMAO, trimethylamine N-oxide; IFN, interferon; SCFAs, short-chain fatty acids; GPR, G-protein coupled receptor; IL, interleukin; Treg, regulatory T cell; Th, T Helper; HDAC, histone deacetylases; TNF, tumor necrosis factor; I3A, indole-3-aldehyde; AHR, aromatic hydrocarbon receptor; I3LA, indole-3-lactic acid; IS, indoxylsulfate; EMT, epithelial-mesenchymal transition.

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 BioRender.com. 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.

Figure 4

Microbial metabolites promote the transformation of the TME from a 'cold' environment to a 'hot' environment, enhancing the efficacy of immunotherapy. When used alone, UroA can reduce the number of M2 macrophages in the TME, increase the infiltration of CD4⁺ T cells and CD8⁺ T cells, and downregulate the expression of PD-1 on CD8⁺ T cells. SCFAs can directly reduce the accumulation of tumor-specific and memory T cells, increase the proportion of Tregs and inhibit the efficacy of immunotherapy. LPS promotes the secretion of IL-6 by tumor cells, activates the JAK/STAT signaling pathway and reduces efficacy of immunotherapy. LPS and butyric acid respectively promote and inhibit the secretion of IL-12 by M1 macrophages, affecting the differentiation of CD8⁺ T cells and CD4⁺ T cells, and regulating the infiltration of Tregs. Adenosine, in the presence of exogenous IFN-γ, binds to A2AR on CD4⁺ T cells, promoting the accumulation of memory T cells. The figure was created using BioRender.com. TME, tumor microenvironment; UroA, urolithin A; PD-1, programmed cell death protein 1; SCFAs, short-chain fatty acids; Treg, regulatory T cell; LPS, lipopolysaccharide; IL, interleukin; IFN, interferon; A_2AR, adenosine A2A receptor.