TCF1高祖CD8 T细胞介导免疫治疗的疗效；然而，人们对控制其产生和维护的机制知之甚少。在这里，我们表明，通过删除丙酮酸激酶肌肉 2 (PKM2) 来靶向糖酵解会导致戊糖磷酸途径 (PPP) 活性升高，从而导致 TCF1high 祖细胞耗尽样表型的富集，并增加体内对 PD-1 阻断的反应性。通过 1,2-13C 葡萄糖碳示踪测定，PKM2KO CD8 T 细胞显示糖酵解通量减少、糖酵解中间体和 PPP 代谢物的积累以及 PPP 循环增加。没有急性糖酵解损伤的 PPP 的小分子激动作用使 CD8 T 细胞偏向 TCF1 高群体，产生了独特的转录景观，并且激动剂处理的 CD8 T 细胞的过继转移与 PD-1 阻断相结合增强了小鼠的肿瘤控制并促进了肿瘤杀伤在患者来源的肿瘤类器官中。我们的研究展示了一种新的代谢重编程，有助于形成类似祖细胞的 T 细胞状态，从而促进免疫治疗的功效。© 2024。作者获得 Springer Nature America, Inc. 的独家许可。

TCF1high progenitor CD8+ T cells mediate the efficacy of immunotherapy; however, the mechanisms that govern their generation and maintenance are poorly understood. Here, we show that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1high progenitor-exhausted-like phenotype and increased responsiveness to PD-1 blockade in vivo. PKM2KO CD8+ T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites and increased PPP cycling as determined by 1,2-13C glucose carbon tracing. Small molecule agonism of the PPP without acute glycolytic impairment skewed CD8+ T cells toward a TCF1high population, generated a unique transcriptional landscape and adoptive transfer of agonist-treated CD8+ T cells enhanced tumor control in mice in combination with PD-1 blockade and promoted tumor killing in patient-derived tumor organoids. Our study demonstrates a new metabolic reprogramming that contributes to a progenitor-like T cell state promoting immunotherapy efficacy.© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.