近日，美国匹兹堡大学医学院教授Marlies Meisel及其小组的研究显示，运动诱导的微生物代谢物增强CD8 T细胞抗肿瘤免疫，促进免疫治疗效果。这一研究成果于2025年7月9日发表在国际顶尖学术期刊《细胞》上。
该团队发现肠道微生物群在运动如何改善临床前黑色素瘤的ICI疗效方面起着关键作用。他们的研究表明，运动刺激微生物的单碳代谢，增加代谢物甲酸的水平，从而增强细胞毒性CD8 T细胞（Tc1）介导的ICI功效。该课题组研究人员进一步证实，微生物来源的甲酸盐在体外增强Tc1细胞命运和体内促进肿瘤抗原特异性Tc1免疫是充分和必需的。在机制上，该团队发现转录因子核因子红系2相关因子2 （Nrf2）在体外是甲酸驱动的Tc1功能增强的关键介质，在体内是运动介导的抗肿瘤作用的关键参与者。最后，该团队发现人类微生物群衍生的甲酸是增强Tc1介导的抗肿瘤免疫的潜在生物标志物，支持其在黑色素瘤抑制中的功能作用。
研究人员表示，运动可以提高免疫检查点抑制剂（ICI）在黑色素瘤等癌症中的疗效；然而，运动介导这种抗肿瘤作用的机制仍不清楚。
附：英文原文
Title: Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy
Author: Catherine M. Phelps, Nathaniel B. Willis, Tingting Duan, Amanda H. Lee, Yue Zhang, Daphne M. Rodriguez J, Surya P. Pandey, Colin R. Laughlin, Aaron B.I. Rosen, Alex C. McPherson, Jake H. Shapira, Simran K. Randhawa, Lee Hedden, Tanner G. Richie, Hallie M. Wiechman, Mackenzie J. Bender, Ina Nemet, Patrick A. Zhrer, Rachel A. Gottschalk, Kathryn H. Schmitz, Steven J. Mullett, Stacy L. Gelhaus, Diwakar Davar, Hassane M. Zarour, Reinhard Hinterleitner, Thomas Mossington, Jonathan H. Badger, Richard R. Rodrigues, John A. McCulloch, Sonny T.M. Lee, Karl-Heinz Wagner, Maria G. Winter, Sebastian E. Winter, Jishnu Das, Joseph F. Pierre, Giorgio Trinchieri, Marlies Meisel
Issue&Volume: 2025-07-09
Abstract: Exercise improves immune checkpoint inhibitor (ICI) efficacy in cancers such as melanoma; however, the mechanisms through which exercise mediates this antitumor effect remain obscure. Here, we identify that the gut microbiota plays a critical role in how exercise improves ICI efficacy in preclinical melanoma. Our study demonstrates that exercise stimulates microbial one-carbon metabolism, increasing levels of the metabolite formate, which subsequently enhances cytotoxic CD8 T cell (Tc1)-mediated ICI efficacy. We further establish that microbiota-derived formate is both sufficient and required to enhance Tc1 cell fate in vitro and promote tumor antigen-specific Tc1 immunity in vivo. Mechanistically, we identify the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) as a crucial mediator of formate-driven Tc1 function enhancement in vitro and a key player in the exercise-mediated antitumor effect in vivo. Finally, we uncover human microbiota-derived formate as a potential biomarker of enhanced Tc1-mediated antitumor immunity, supporting its functional role in melanoma suppression.
DOI: 10.1016/j.cell.2025.06.018
Source: https://www.cell.com/cell/abstract/S0092-8674(25)00684-1