Acetate Promotes T Cell Effector Function during Glucose Restriction

Competition for nutrients like glucose can metabolically restrict T cells and contribute to their hyporesponsiveness during cancer. Metabolic adaptation to the surrounding microenvironment is therefore key for maintaining appropriate cell function. For instance, cancer cells use acetate as a substrate alternative to glucose to fuel metabolism and growth. Here, we show that acetate rescues effector function in glucose-restricted CD8⁺ T cells. Mechanistically, acetate promotes histone acetylation and chromatin accessibility and enhances IFN-γ gene transcription and cytokine production in an acetyl-CoA synthetase (ACSS)-dependent manner. Ex vivo acetate treatment increases IFN-γ production by exhausted T cells, whereas reducing ACSS expression in T cells impairs IFN-γ production by tumor-infiltrating lymphocytes and tumor clearance. Thus, hyporesponsive T cells can be epigenetically remodeled and reactivated by acetate, suggesting that pathways regulating the use of substrates alternative to glucose could be therapeutically targeted to promote T cell function during cancer. Qiu et al. show that acetate enhances histone acetylation, chromatin accessibility, and effector function in glucose-restricted CD8⁺ T cells. The authors find that manipulation of acetate-handling pathways influences cytokine production of tumor-infiltrating CD8⁺ T cells, which could have therapeutic implications for activating CD8⁺ T cell effector function in the tumor microenvironment.