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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., Competing Interests: Declaration of interests M.W. and P.R. are inventors on a patent application related to these findings and have research collaborations with MPC Therapeutics, with P.R. being a member of the advisory board. D.M. is an inventor on patents related to CAR T cell therapy, filed by the University of Pennsylvania and the University of Geneva, and is a consultant for Limula Therapeutics and MPC Therapeutics. P.-C.H. is scientific advisory for Elixiron Immunotherapeutics, Acepodia, and Novartis. P.-C.H. also receives research support from Elixiron Immunotherapeutics. S.Y.L. is a consultant to Senda Biosciences., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)