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

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

doi:10.1016/j.cell.2025.06.018

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

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

Veröffentlichungen: Beitrag in Fachzeitschrift › Artikel › Peer Reviewed

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.

Originalsprache	Englisch
Seiten (von - bis)	5680-5700.e28
Fachzeitschrift	Cell
Jahrgang	188
Ausgabenummer	20
Frühes Online-Datum	4 Juli 2025
DOIs	https://doi.org/10.1016/j.cell.2025.06.018
Publikationsstatus	Veröffentlicht - 2 Okt. 2025

Fördermittel

We thank the University of Pittsburgh’s Unified Flow Core, Health Sciences Mass Spectrometry Core, and Gnotobiotic Core for their services. We thank the NIH Tetramer Core Facility. Schematics were created with BioRender.com. This work was supported by an Investigator Start-up Fund , Department of Immunology, University of Pittsburgh School of Medicine to M.M. and R.H.; NIH/NIDDK - R01DK130897 , NIH/NCI - R01CA293654 , NIH/NCI - R21CA259636 , and MRA award ( https://doi.org/10.48050/pc.gr.143738 ) 820677 and SPORE-NIH P50CA254865 grant to M.M.; NIH - T32 CA082084 to A.C.M., A.H.L., and C.M.P.; NIH - F32CA284780 to T.D.; NIH - F31CA290756 to C.M.P.; NIH/NHLBI - R01HL160747 to I.N.; NIH - R01HL162658 to R.A.G.; NIH - T32DK007665 to N.B.W.; Vienna Doctoral School of Pharmaceutical, Nutritional, and Sport Sciences’ Completion Grant of the University of Vienna to P.A.Z.; University of Vienna (Research Platform Active Ageing) and the EU program Interreg SK-AT (NutriAging) support to K.-H.W.; NIH ( AI118807 , DK138912 , and AI188307 ), Burroughs Wellcome Fund ( 1017880 ), and US-Israel Binational Science Foundation ( 2021025 ) to S.E.W.; NIH - R01AI168478 and R21AI163721 and Hillman-Developmental Pilot-Award ( NIH - P30CA047904 ) to R.H.; NIH/NIAID - DP2AI164325 to J.D.; S10OD023402 and S10OD032141 to S.L.G; Intramural NCI-NIH Research Program -support to T.M., J.H.B., R.R.R., J.A.M., and G.T.; K-INBRE grant P20GM103418 and Kansas State University Johnson Cancer Research Center Expansion and Innovation Award to S.T.M.L., T.G.R. and H.M.W.; and NIH R01CA253329 and U01CA272541 to J.F.P. We thank the University of Pittsburgh's Unified Flow Core, Health Sciences Mass Spectrometry Core, and Gnotobiotic Core for their services. We thank the NIH Tetramer Core Facility. Schematics were created with BioRender.com. This work was supported by an Investigator Start-up Fund, Department of Immunology, University of Pittsburgh School of Medicine to M.M. and R.H.; NIH/NIDDK-R01DK130897, NIH/NCI-R01CA293654, NIH/NCI-R21CA259636, and MRA award (https://doi.org/10.48050/pc.gr.143738) 820677 and SPORE-NIH P50CA254865 grant to M.M.; NIH-T32 CA082084 to A.C.M., A.H.L., and C.M.P.; NIH-F32CA284780 to T.D.; NIH-F31CA290756 to C.M.P.; NIH/NHLBI-R01HL160747 to I.N.; NIH-R01HL162658 to R.A.G.; NIH-T32DK007665 to N.B.W.; Vienna Doctoral School of Pharmaceutical, Nutritional, and Sport Sciences’ Completion Grant of the University of Vienna to P.A.Z.; University of Vienna (Research Platform Active Ageing) and the EU program Interreg SK-AT (NutriAging) support to K.-H.W.; NIH (AI118807, DK138912, and AI188307), Burroughs Wellcome Fund (1017880), and US-Israel Binational Science Foundation (2021025) to S.E.W.; NIH-R01AI168478 and R21AI163721 and Hillman-Developmental Pilot-Award (NIH-P30CA047904) to R.H.; NIH/NIAID-DP2AI164325 to J.D.; S10OD023402 and S10OD032141 to S.L.G; Intramural NCI-NIH Research Program-support to T.M., J.H.B., R.R.R., J.A.M., and G.T.; K-INBRE grant P20GM103418 and Kansas State University Johnson Cancer Research Center Expansion and Innovation Award to S.T.M.L., T.G.R. and H.M.W.; and NIH R01CA253329 and U01CA272541 to J.F.P.

UN SDGs

Dieser Output leistet einen Beitrag zu folgendem(n) Ziel(en) für nachhaltige Entwicklung

SDG 3 – Gesundheit und Wohlergehen

ÖFOS 2012

303009 Ernährungswissenschaften

Zugriff auf Dokument

10.1016/j.cell.2025.06.018

Andere Dateien und Links

Verknüpfung zur Publikation in Scopus

Zitationsweisen

Phelps, C. M., Willis, N. B., Duan, T., Lee, A. H., Zhang, Y., Rodriguez J, D. M., Pandey, S. P., Laughlin, C. R., Rosen, A. B. I., McPherson, A. C., Shapira, J. H., Randhawa, S. K., Hedden, L., Richie, T. G., Wiechman, H. M., Bender, M. J., Nemet, I., Zöhrer, P. A., Gottschalk, R. A., ... Meisel, M. (2025). Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy. Cell, 188(20), 5680-5700.e28. https://doi.org/10.1016/j.cell.2025.06.018

@article{e6ec72876cf0418aa41ec0ba0d632732,

title = "Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy",

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 = "microbiota, formate, immune checkpoint inhibitor, microbiota metabolite, Nrf2, exercise, melanoma, FMT, CD8 T cells",

author = "Phelps, \{Catherine M\} and Willis, \{Nathaniel B\} and Tingting Duan and Lee, \{Amanda H\} and Yue Zhang and \{Rodriguez J\}, \{Daphne M\} and Pandey, \{Surya P\} and Laughlin, \{Colin R\} and Rosen, \{Aaron B I\} and McPherson, \{Alex C\} and Shapira, \{Jake H\} and Randhawa, \{Simran K\} and Lee Hedden and Richie, \{Tanner G\} and Wiechman, \{Hallie M\} and Bender, \{Mackenzie J\} and Ina Nemet and Z{\"o}hrer, \{Patrick A\} and Gottschalk, \{Rachel A\} and Schmitz, \{Kathryn H\} and Mullett, \{Steven J\} and Gelhaus, \{Stacy L\} and Diwakar Davar and Zarour, \{Hassane M\} and Reinhard Hinterleitner and Thomas Mossington and Badger, \{Jonathan H\} and Rodrigues, \{Richard R\} and McCulloch, \{John A\} and Lee, \{Sonny T M\} and Karl-Heinz Wagner and Winter, \{Maria G\} and Winter, \{Sebastian E\} and Jishnu Das and Pierre, \{Joseph F\} and Giorgio Trinchieri and Marlies Meisel",

note = "Publisher Copyright: {\textcopyright} 2025 Elsevier Inc.",

year = "2025",

month = oct,

day = "2",

doi = "10.1016/j.cell.2025.06.018",

language = "English",

volume = "188",

pages = "5680--5700.e28",

journal = "Cell",

issn = "0092-8674",

publisher = "CELL PRESS",

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Phelps, CM, Willis, NB, Duan, T, Lee, AH, Zhang, Y, Rodriguez J, DM, Pandey, SP, Laughlin, CR, Rosen, ABI, McPherson, AC, Shapira, JH, Randhawa, SK, Hedden, L, Richie, TG, Wiechman, HM, Bender, MJ, Nemet, I, Zöhrer, PA, Gottschalk, RA, Schmitz, KH, Mullett, SJ, Gelhaus, SL, Davar, D, Zarour, HM, Hinterleitner, R, Mossington, T, Badger, JH, Rodrigues, RR, McCulloch, JA, Lee, STM, Wagner, K-H, Winter, MG, Winter, SE, Das, J, Pierre, JF, Trinchieri, G & Meisel, M 2025, 'Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy', Cell, Jg. 188, Nr. 20, S. 5680-5700.e28. https://doi.org/10.1016/j.cell.2025.06.018

TY - JOUR

T1 - Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy

AU - Phelps, Catherine M

AU - Willis, Nathaniel B

AU - Duan, Tingting

AU - Lee, Amanda H

AU - Zhang, Yue

AU - Rodriguez J, Daphne M

AU - Pandey, Surya P

AU - Laughlin, Colin R

AU - Rosen, Aaron B I

AU - McPherson, Alex C

AU - Shapira, Jake H

AU - Randhawa, Simran K

AU - Hedden, Lee

AU - Richie, Tanner G

AU - Wiechman, Hallie M

AU - Bender, Mackenzie J

AU - Nemet, Ina

AU - Zöhrer, Patrick A

AU - Gottschalk, Rachel A

AU - Schmitz, Kathryn H

AU - Mullett, Steven J

AU - Gelhaus, Stacy L

AU - Davar, Diwakar

AU - Zarour, Hassane M

AU - Hinterleitner, Reinhard

AU - Mossington, Thomas

AU - Badger, Jonathan H

AU - Rodrigues, Richard R

AU - McCulloch, John A

AU - Lee, Sonny T M

AU - Wagner, Karl-Heinz

AU - Winter, Maria G

AU - Winter, Sebastian E

AU - Das, Jishnu

AU - Pierre, Joseph F

AU - Trinchieri, Giorgio

AU - Meisel, Marlies

PY - 2025/10/2

Y1 - 2025/10/2

N2 - 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.

AB - 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.

KW - microbiota

KW - formate

KW - immune checkpoint inhibitor

KW - microbiota metabolite

KW - Nrf2

KW - exercise

KW - melanoma

KW - FMT

KW - CD8 T cells

UR - https://www.scopus.com/pages/publications/105010342799

U2 - 10.1016/j.cell.2025.06.018

DO - 10.1016/j.cell.2025.06.018

M3 - Article

C2 - 40639377

SN - 0092-8674

VL - 188

SP - 5680-5700.e28

JO - Cell

JF - Cell

IS - 20

ER -

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

Abstract

Fördermittel

UN SDGs

ÖFOS 2012

Zugriff auf Dokument

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