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

Catherine M Phelps¹, Nathaniel B Willis², Tingting Duan³, Amanda H Lee¹, Yue Zhang⁴, Daphne M Rodriguez J³, Surya P Pandey³, Colin R Laughlin³, Aaron B I Rosen⁵, Alex C McPherson⁶, Jake H Shapira³, Simran K Randhawa³, Lee Hedden³, Tanner G Richie⁷, Hallie M Wiechman⁷, Mackenzie J Bender³, Ina Nemet⁸, Patrick A Zöhrer⁹, Rachel A Gottschalk¹⁰, Kathryn H Schmitz¹¹, Steven J Mullett¹², Stacy L Gelhaus¹², Diwakar Davar¹³, Hassane M Zarour¹⁴, Reinhard Hinterleitner¹⁵, Thomas Mossington¹⁶, Jonathan H Badger¹⁶, Richard R Rodrigues¹⁷, John A McCulloch¹⁶, Sonny T M Lee⁷, Karl-Heinz Wagner¹⁸, Maria G Winter¹⁹, Sebastian E Winter¹⁹, Jishnu Das¹⁰, Joseph F Pierre²⁰, Giorgio Trinchieri²¹, Marlies Meisel²²

Affiliations

¹ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Graduate Program of Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
² Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA.
³ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁴ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Tsinghua Medicine, School of Medicine, Tsinghua University, Beijing, China.
⁵ Center for Systems Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Joint CMU-Pitt PhD Program in Computational Biology, Carnegie Mellon-University of Pittsburgh, Pittsburgh, PA, USA.
⁶ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Infectious Diseases and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA.
⁷ Division of Biology, Kansas State University, Manhattan, KS, USA.
⁸ Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome & Human Health, Cleveland Clinic, Cleveland, OH, USA.
⁹ Department of Nutritional Sciences, University of Vienna, Vienna, Austria; Vienna Doctoral School of Pharmaceutical, Nutritional and Sport Sciences (PhaNuSpo), University of Vienna, Vienna, Austria.
¹⁰ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Systems Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹¹ Department of Medicine and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
¹² Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA, USA.
¹³ Department of Medicine and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
¹⁴ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Medicine and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
¹⁵ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Institute of Infection, Inflammation, and Immunity, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
¹⁶ Genetics and Microbiome Core, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
¹⁷ 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.
¹⁸ Department of Nutritional Sciences, University of Vienna, Vienna, Austria; Research Platform Active Ageing, University of Vienna, Vienna, Austria.
¹⁹ Department of Internal Medicine, Division of Infectious Diseases, University of California, Davis, Davis, CA, USA.
²⁰ Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA; Department of Surgery, University of Wisconsin-Madison, Madison, WI, USA.
²¹ 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.
²² Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Electronic address: marlies@pitt.edu.

PMID: 40639377
PMCID: PMC12258965 (available on 2026-07-04)
DOI: 10.1016/j.cell.2025.06.018

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

Catherine M Phelps et al. Cell. 2025.

. 2025 Jul 4:S0092-8674(25)00684-1.

doi: 10.1016/j.cell.2025.06.018. Online ahead of print.

Authors

Affiliations

¹ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Graduate Program of Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
² Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA.
³ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁴ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Tsinghua Medicine, School of Medicine, Tsinghua University, Beijing, China.
⁵ Center for Systems Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Joint CMU-Pitt PhD Program in Computational Biology, Carnegie Mellon-University of Pittsburgh, Pittsburgh, PA, USA.
⁶ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Infectious Diseases and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA.
⁷ Division of Biology, Kansas State University, Manhattan, KS, USA.
⁸ Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome & Human Health, Cleveland Clinic, Cleveland, OH, USA.
⁹ Department of Nutritional Sciences, University of Vienna, Vienna, Austria; Vienna Doctoral School of Pharmaceutical, Nutritional and Sport Sciences (PhaNuSpo), University of Vienna, Vienna, Austria.
¹⁰ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Systems Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹¹ Department of Medicine and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
¹² Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA, USA.
¹³ Department of Medicine and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
¹⁴ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Medicine and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
¹⁵ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Institute of Infection, Inflammation, and Immunity, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
¹⁶ Genetics and Microbiome Core, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
¹⁷ 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.
¹⁸ Department of Nutritional Sciences, University of Vienna, Vienna, Austria; Research Platform Active Ageing, University of Vienna, Vienna, Austria.
¹⁹ Department of Internal Medicine, Division of Infectious Diseases, University of California, Davis, Davis, CA, USA.
²⁰ Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA; Department of Surgery, University of Wisconsin-Madison, Madison, WI, USA.
²¹ 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.
²² Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Electronic address: marlies@pitt.edu.

PMID: 40639377
PMCID: PMC12258965 (available on 2026-07-04)
DOI: 10.1016/j.cell.2025.06.018

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.

Keywords: CD8 T cells; FMT; Nrf2; exercise; formate; immune checkpoint inhibitor; melanoma; microbiota; microbiota metabolite.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

References

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials