Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy

IF 45.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Cell Pub Date : 2025-07-09 DOI:10.1016/j.cell.2025.06.018
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. Zöhrer, Rachel A. Gottschalk, Kathryn H. Schmitz, Marlies Meisel
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引用次数: 0

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.

Abstract Image

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
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。在这里,我们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。我们的研究表明,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。我们进一步证实,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,我们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,我们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。
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来源期刊
Cell
Cell 生物-生化与分子生物学
CiteScore
110.00
自引率
0.80%
发文量
396
审稿时长
2 months
期刊介绍: Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.
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