明尼苏达大学Vivek Verma研究团队在研究中取得进展。他们研究出丙酮酸激酶M2激活可重编程CD8 T细胞中的线粒体，增强抗PD1治疗的效应功能和疗效。2025年4月7日出版的《细胞—代谢》杂志发表了这项成果。

研究人员发现，丙酮酸激酶M2（PKM2）的激活增强了CD8和嵌合抗原受体(CAR)-T细胞中线粒体依赖性效应的功能。多组学和¹³C-葡萄糖示踪研究表明，PKM2激动作用改变了单碳代谢，降低了蛋氨酸水平，导致核和线粒体DNA低甲基化，增强了线粒体的生物发生和功能。PKM2激活增加了CD8 T细胞的回忆反应和抗肿瘤功能，增强了过继细胞治疗。在临床前模型中，PKM2激动剂诱导CD8 T细胞依赖性抗肿瘤反应，与抗程序性死亡1 （PD1）治疗协同。

在免疫学上，PKM2激动剂促进了效应T细胞的激活，同时减少了肿瘤中的FoxP3⁺ T调节细胞（Treg）。抗PD1组合增强了肿瘤特异性活化CD8 T细胞的频率。总之，PKM2激动作用增加了线粒体功能，支持细胞毒性。因此，PKM2的药理学靶向可以成为增强过继细胞治疗、原位抗肿瘤免疫反应和免疫检查点阻断治疗的临床可行策略。

据悉，线粒体调节T细胞功能和对免疫治疗的反应。

附：英文原文

Title: Pyruvate kinase M2 activation reprograms mitochondria in CD8 T cells, enhancing effector functions and efficacy of anti-PD1 therapy

Author: Seyedeh Sahar Mortazavi Farsani, Jignesh Soni, Lu Jin, Anil Kumar Yadav, Shivani Bansal, Tian Mi, Leena Hilakivi-Clarke, Robert Clarke, Benjamin Youngblood, Amrita Cheema, Vivek Verma

Issue&Volume: 2025-04-07

Abstract: Mitochondria regulate T cell functions and response to immunotherapy. We show that pyruvate kinase M2 (PKM2) activation enhances mitochondria-dependent effector functions in CD8 and chimeric antigen receptor (CAR)-T cells. Multi-omics and 13C-glucose tracer studies showed that PKM2 agonism alters one-carbon metabolism, decreasing methionine levels, resulting in hypomethylated nuclear and mitochondrial DNA and enhancing mitochondrial biogenesis and functions. PKM2 activation increased the recall responses and anti-tumor functions of CD8 T cells, enhancing adoptive cell therapy. In preclinical models, the PKM2 agonist induced CD8 T cell-dependent anti-tumor responses that synergized with anti-programmed death 1 (PD1) therapy. Immunologically, PKM2 agonists boosted the activation of effector T cells while reducing FoxP3+ T regulatory (Treg) cells in the tumors. The anti-PD1 combination enhanced the frequency of tumor-specific activated CD8 T cells. Together, PKM2 agonism increased mitochondrial functions supporting cell cytotoxicity. Hence, pharmacological targeting of PKM2 can be a clinically viable strategy for enhancement of adoptive cell therapy, in situ anti-tumor immune responses, and immune checkpoint blockade therapy.

DOI: 10.1016/j.cmet.2025.03.003

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(25)00106-8