Abstract Lactate is a key metabolite produced from glycolytic metabolism of glucose molecules, yet it also serves as a primary carbon fuel source for many cell types. In the tumor-immune microenvironment, effect of lactate on cancer and immune cells can be highly complex and hard to decipher, which is further confounded by acidic protons, a co-product of glycolysis. Here we show that lactate is able to increase stemness of CD8 + T cells and augments anti-tumor immunity. Subcutaneous administration of sodium lactate but not glucose to mice bearing transplanted MC38 tumors results in CD8 + T cell-dependent tumor growth inhibition. Single cell transcriptomics analysis reveals increased proportion of stem-like TCF-1-expressing CD8 + T cells among intra-tumoral CD3 + cells, a phenotype validated by in vitro lactate treatment of T cells. Mechanistically, lactate inhibits histone deacetylase activity, which results in increased acetylation at H3K27 of the Tcf7 super enhancer locus, leading to increased Tcf7 gene expression. CD8 + T cells in vitro pre-treated with lactate efficiently inhibit tumor growth upon adoptive transfer to tumor-bearing mice. Our results provide evidence for an intrinsic role of lactate in anti-tumor immunity independent of the pH-dependent effect of lactic acid, and might advance cancer immune therapy.

Lactate increases stemness of CD8 + T cells to augment anti-tumor immunity