Wenes, MathiasJaccard, AlisonWyss, TaniaMaldonado-Pérez, NoeliaTeoh, Shao ThingLepez, AnoukRenaud, FabriceFranco, FabienWaridel, PatriceYacoub Maroun, CélineTschumi, BenjaminDumauthioz, NinaZhang, LianjunDonda, AlenaMartín, FranciscoMigliorini, DenisLunt, Sophia YHo, Ping-ChihRomero, Pedro2023-05-032023-05-032022-04-21http://hdl.handle.net/10668/22118Glycolysis, 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.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/T cell memorychimeric antigen receptor T cell therapyimmunometabolismmitochondrial pyruvate carriertumor-infiltrating lymphocyte metabolismLactatesMemory T CellsMitochondriaMitochondrial Membrane Transport ProteinsMonocarboxylic Acid TransportersPyruvic Acidresearch article35452600open access10.1016/j.cmet.2022.03.0131932-7420PMC9116152http://www.cell.com/article/S1550413122001279/pdf