Fig. 3

Double-edged swords in cancer immunometabolism. Implications of FA synthesis (1) and catabolism (2) on tumor progression. 1) Upregulation of SREBP activity in T_reg cells synergizes with FASN to promote FA synthesis, which in turn activates the PI3K pathway and facilitates the maturation of T_reg cells. Specific deletion of SCAP (an essential factor for SREBP activity) by T_reg cells enhances anti-PD-1 immunotherapy; 2) Leptin downregulates CD8⁺ T cell effector function through activation of STAT3-FAO and inhibition of glycolysis. Ablating T cell STAT3 or treatment with perhexiline (FTO inhibitor) in obese mice spontaneously developing breast tumor reduces FAO, increases glycolysis and CD8⁺ T effector cell functions, leading to inhibition of breast tumor development. Additionally, the effects of lactate on cancer and immune cells in TME can be complex and difficult to decipher, which is further confounded by acid protons (byproducts of glycolysis). 3) Tumor-derived lactate is an inhibitor of CD8⁺ T cell cytotoxicity. Cytotoxic T cells shunt succinate out of the TCA circulation to promote autocrine signalling via the succinate receptor (SUCNR1). Moreover, cytotoxic T cells rely on PC to replenish succinate. Lactate decreases PC activity, and similarly, inhibition of PDH restores PC activity, succinate secretion, and SUCNR1 activation; 4) Lactate increases CD8⁺ T cell stemness and enhances anti-tumor immunity. Subcutaneous injection of lactate in mice transplanted with MC38 tumors leads to CD8⁺ T cell-dependent tumor growth inhibition. Mechanistically, lactate inhibits histone deacetylase activity, leading to increased acetylation of the Tcf7 super-enhancer site, H3K27, which results in increased Tcf7 gene expression. FA, fatty acid; SREBP, sterol regulatory element binding protein; FASN, fatty acid synthase; PI3K, phosphatidylinositol 3-kinase; FAO, fatty acid oxidation; TME, tumor microenvironment; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase