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.

糖酵解，包括乳酸发酵和丙酮酸氧化，协调 CD8 ⁺ T 细胞分化。然而，线粒体丙酮酸载体 (MPC) 控制的线粒体丙酮酸代谢和摄取如何影响 T 细胞功能和命运仍然难以捉摸。我们发现 MPC 的基因缺失驱动 CD8 ⁺ T 细胞向记忆表型分化。MPC 抑制诱导的代谢灵活性促进了谷氨酰胺和脂肪酸氧化产生的乙酰辅酶 A，从而增强了前记忆基因的组蛋白乙酰化和染色质可及性。然而，在肿瘤微环境中，MPC 对于维持乳酸氧化以支持 CD8 ^{+至关重要}T细胞抗肿瘤功能。我们进一步揭示了用 MPC 抑制剂制造嵌合抗原受体 (CAR) T 细胞会留下记忆表型，并证明注入 MPC 抑制剂条件化的 CAR T 细胞会产生优异且持久的抗肿瘤活性。总之，我们发现线粒体丙酮酸摄取指导代谢灵活性以指导 T 细胞分化和抗肿瘤反应。