Fig. 4.

Microbe-derived metabolites modulate the tumor immune microenvironment. Microbial metabolites, such as short-chain fatty acids, bile acids, and inosine, can enter to blood and modulate the tumor immune microenvironment. Butyric acid, a member of short-chain fatty acids, increases the level of IL-10 and retinoic acid in the intestinal microenvironment, which promotes regulatory T cells differentiation and proliferation. Butyrate-mediated HDACs inhibition leads to up-regulation of the transcriptional regulator ID2 and thus upgrading the IL-12R signaling pathway in CD8⁺ T cells. Secondary bile acids are produced by gut microorganisms from primary bile acids. ω-murocholic acid, a member of secondary bile acids, down-regulates CXCL16 secretion and reduces natural killer T cells and CD4⁺ T cells recruitment. Inosine binds to A2AR on T cells and initiates the inosine-A2AR-cAMP-PKA signaling pathway. With the costimulatory effects from the dendritic cells, inosine induces naïve T cells to differentiate into Th1. Besides, Inosine is alternative energy of glucose in cytotoxic T cells. Abbreviations: A2AR = adenosine 2A receptor, CXCL = the chemokine (C-X-C motif) ligand, CXCR = the chemokine (C-X-C motif) receptor, HDAC = histone deacetylase, GPR = G protein-coupled receptor, Th1 = helper 1 T cell