Memory CD8 T cells can provide long-term protection against tumors, which depends on their enhanced proliferative capacity, self-renewal and unique metabolic rewiring to sustain cellular fitness. Specifically, memory CD8 T cells engage oxidative phosphorylation and fatty acid oxidation to fulfill their metabolic demands. In contrast, tumor-infiltrating lymphocytes (TILs) display severe metabolic defects, which may underlie their functional decline. Here, we show that overexpression of proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), the master regulator of mitochondrial biogenesis (MB), favors CD8 T cell central memory formation rather than resident memory generation. PGC-1α-overexpressing CD8 T cells persist and mediate more robust recall responses to bacterial infection or peptide vaccination. Importantly, CD8 T cells with enhanced PGC-1α expression provide stronger antitumor immunity in a mouse melanoma model. Moreover, TILs overexpressing PGC-1α maintain higher mitochondrial activity and improved expansion when rechallenged in a tumor-free host. Altogether, our findings indicate that enforcing mitochondrial biogenesis promotes CD8 T cell memory formation, metabolic fitness, and antitumor immunity in vivo.

记忆 CD8 T 细胞可以提供针对肿瘤的长期保护，这取决于它们增强的增殖能力、自我更新和独特的代谢重新布线以维持细胞适应性。具体来说，记忆 CD8 T 细胞参与氧化磷酸化和脂肪酸氧化以满足其代谢需求。相比之下，肿瘤浸润淋巴细胞 (TIL) 表现出严重的代谢缺陷，这可能是其功能下降的基础。在这里，我们表明增殖物激活受体 γ 共激活因子 1-α (PGC-1α) 是线粒体生物发生 (MB) 的主要调节因子的过度表达，有利于 CD8 T 细胞中央记忆的形成，而不是常驻记忆的产生。过表达 PGC-1α 的 CD8 T 细胞持续存在并介导对细菌感染或肽疫苗接种的更强烈的回忆反应。重要的，具有增强 PGC-1α 表达的 CD8 T 细胞在小鼠黑色素瘤模型中提供更强的抗肿瘤免疫。此外，过表达 PGC-1α 的 TIL 在无肿瘤宿主中再次受到攻击时可保持更高的线粒体活性并改善扩增。总之，我们的研究结果表明，强制线粒体生物发生可促进 CD8 T 细胞记忆形成、代谢适应性和体内抗肿瘤免疫。