Acetate Promotes T Cell Effector Function during Glucose Restriction

TLDR

Competition for glucose limits T cell function, and metabolic adaptation—such as using acetate as an alternative fuel—is crucial for maintaining immune activity in the tumor microenvironment. The study investigates whether acetate can restore effector function in glucose‑restricted CD8⁺ T cells. Acetate enhances histone acetylation and chromatin accessibility, boosting IFN‑γ transcription and cytokine production via an acetyl‑CoA synthetase–dependent pathway. Ex vivo acetate treatment elevates IFN‑γ production in exhausted T cells, while ACSS knockdown diminishes IFN‑γ output and tumor clearance, demonstrating that acetate can epigenetically remodel and reactivate hyporesponsive T cells.

Abstract

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.