线粒体丙酮酸载体调控记忆 T 细胞分化和抗肿瘤功能

Glycolysis, including both lactate fermentation and pyruvate oxidation, orchestrates CD8 + T cell differentiation.

However, how mitochondrial pyruvate metabolism and uptake controlled by the mitochondrial pyruvate carrier (MPC) impact T cell function and fate remains elusive.

We found that genetic deletion of MPC drives CD8 + T cell differentiation toward a memory phenotype. Metabolic flexibility induced by MPC inhibition facilitated acetyl-coenzyme-A production by glutamine and fatty acid oxidation that results in enhanced histone acetylation and chromatin accessibility on pro-memory genes.

However, in the tumor microenvironment, MPC is essential for sustaining lactate oxidation to support CD8 + T cell antitumor function.

We further revealed that chimeric antigen receptor (CAR) T cell manufacturing with an MPC inhibitor imprinted a memory phenotype and demonstrated that infusing MPC inhibitor-conditioned CAR T cells resulted in superior and long-lasting antitumor activity. Altogether, we uncover that mitochondrial pyruvate uptake instructs metabolic flexibility for guiding T cell differentiation and antitumor responses.