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

Autor(en)

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, 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

Abstrakt

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.

Organisation(en)

Department für Ernährungswissenschaften, Institut für Bildungswissenschaft

Externe Organisation(en)

University of Pittsburgh School of Medicine, University of Wisconsin, Madison, Kansas State University, Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome & Human Health, Cleveland Clinic, Cleveland, OH, USA., University of Pittsburgh, Genetics and Microbiome Core, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA., Genetics and Microbiome Core, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., University of California, Davis, Genetics and Microbiome Core, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.

Journal

Cell

Band

188

Seiten

5680-5700.e28

ISSN

0092-8674

DOI

https://doi.org/10.1016/j.cell.2025.06.018

Publikationsdatum

07-2025

Peer-reviewed

Ja

ÖFOS 2012

303009 Ernährungswissenschaften

Schlagwörter

ASJC Scopus Sachgebiete

Allgemeine Biochemie, Genetik und Molekularbiologie

Sustainable Development Goals

SDG 3 – Gesundheit und Wohlergehen

Link zum Portal

https://ucrisportal.univie.ac.at/de/publications/e6ec7287-6cf0-418a-a41e-c0ba0d632732