ArticleCell2025
Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy.
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Article in Cell, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers, 1 of them a synthesis that pooled it.
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60citing papers in PubMed, 1 pooled it
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Who cites it
60 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Metabolomics and metabolites in cancer diagnosis and treatment.Molecular biomedicine · 2025Pooled it
- Trial
- Adjuvant penpulimab in very-high risk clear cell renal cell carcinoma: a prospective, non-randomized, controlled phase II trial with integrated plasma multi-omics analyses.Journal for immunotherapy of cancer · 2026Trial
- Dance and Dietary Intervention Improves Metabolic Health, Fitness, and Quality of Life With Modest Gut Microbiota Shifts in Breast Cancer Patients With Obesity: A Pilot RCT.Cancer reports (Hoboken, N.J.) · 2026Trial
- Microbiota as a modulator of drug response: targeting microbial-drug crosstalk in cancer therapy.Gut microbes · 2026Review
- Precision Exercise for Breast Cancer-Related Outcomes: Towards Personalised Training Based on Tumour, Treatment and Patient Characteristics.Sports medicine (Auckland, N.Z.) · 2026Review
- Intratumoral microbiota in cancer immunotherapy: metabolic-epigenetic crosstalk and engineered bacterial therapeutics.Experimental hematology & oncology · 2026Review
- Metabolic immune checkpoints (MICs) in cancer: from molecular mechanisms to challenges and opportunities in clinical translation.Signal transduction and targeted therapy · 2026Review
- Exercise therapy in cancer prevention and treatment.Nature reviews. Clinical oncology · 2026Review
- Review
- Multi-cohort validation ofTranslational cancer research · 2026Article
- Urinary Metabolic Profiles Before and After the Winter Training Season in Female Soccer Players.Metabolites · 2026Article
- FASTINA - protocol for a randomised feasibility trial of time-restricted eating to improve response to multiple myeloma therapy.Pilot and feasibility studies · 2026Article
- Autophagy modulation in cancer.Nature reviews. Drug discovery · 2026Review
- Advances in Exercise-Mediated Regulation of the Gut Microbiota via the Muscle-Gut Axis: Implications for Tumor Immunity and Treatment Responses.Metabolites · 2026Review
- When does exercise hinder rather than halt tumor progression? The decisive role of immunotherapy responsiveness.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Regulation of PD-1PD-L1 Immune Checkpoints by Gut Microbiota Metabolites and Their Clinical Translational Research: A Review.Immunity, inflammation and disease · 2026Review
- A wake-up call for acne.Journal of the European Academy of Dermatology and Venereology : JEADV · 2026Article
- The Influence of Dietary and Physical Exercise Habits on Melanoma Risk: A Case-Control Study.Nutrients · 2026Article
- Harnessing the microbiome for cancer therapy.Nature reviews. Microbiology · 2026Review
Corrections and comments
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Authors and funding
37 authors.
Catherine M PhelpsDepartment 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.
Nathaniel B WillisDepartment of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA.
Tingting DuanDepartment of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Amanda H LeeDepartment 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.
Yue ZhangDepartment of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Tsinghua Medicine, School of Medicine, Tsinghua University, Beijing, China.
Daphne M Rodriguez JDepartment of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Surya P PandeyDepartment of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Colin R LaughlinDepartment of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Aaron B I RosenCenter 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.
Alex C McPhersonDepartment 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.
Jake H ShapiraDepartment of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Simran K RandhawaDepartment of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Lee HeddenDepartment of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Tanner G RichieDivision of Biology, Kansas State University, Manhattan, KS, USA.
Hallie M WiechmanDivision of Biology, Kansas State University, Manhattan, KS, USA.
Mackenzie J BenderDepartment of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Ina NemetDepartment of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome & Human Health, Cleveland Clinic, Cleveland, OH, USA.
Patrick A ZöhrerDepartment of Nutritional Sciences, University of Vienna, Vienna, Austria; Vienna Doctoral School of Pharmaceutical, Nutritional and Sport Sciences (PhaNuSpo), University of Vienna, Vienna, Austria.
Rachel A GottschalkDepartment of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Systems Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Kathryn H SchmitzDepartment of Medicine and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
Steven J MullettDepartment 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.
Stacy L GelhausDepartment 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.
Diwakar DavarDepartment 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.
Hassane M ZarourDepartment 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.
Reinhard HinterleitnerDepartment 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.
Thomas MossingtonGenetics and Microbiome Core, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Jonathan H BadgerGenetics and Microbiome Core, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Richard R RodriguesGenetics 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.
John A McCullochGenetics and Microbiome Core, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Sonny T M LeeDivision of Biology, Kansas State University, Manhattan, KS, USA.
Karl-Heinz WagnerDepartment of Nutritional Sciences, University of Vienna, Vienna, Austria; Research Platform Active Ageing, University of Vienna, Vienna, Austria.
Maria G WinterDepartment of Internal Medicine, Division of Infectious Diseases, University of California, Davis, Davis, CA, USA.
Sebastian E WinterDepartment of Internal Medicine, Division of Infectious Diseases, University of California, Davis, Davis, CA, USA.
Jishnu DasDepartment of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Systems Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Joseph F PierreDepartment of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA; Department of Surgery, University of Wisconsin-Madison, Madison, WI, USA.
Giorgio TrinchieriGenetics 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.
Marlies MeiselDepartment 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.
Funding
VECTOR CORE FACILITYP30CA047904 · NCI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI JOHN C. BYRD · 1988 to 2026
$158.0MMentoring CoreP20GM103418 · NIGMS · UNIVERSITY OF KANSAS MEDICAL CENTER · PI Douglas E Wright · 2012 to 2026
$63.0MProject 5: Microenvironment manipulation using anti-angiogenics to improve immunotherapy in melanomaP50CA254865 · NCI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI DELGOFFE, GREG M., KIRKWOOD, JOHN MUNN · 2021 to 2025
$10.4MTRAINING IN NUTRITIONT32DK007665 · NIDDK · UNIVERSITY OF WISCONSIN-MADISON · PI GUY E GROBLEWSKI, Chi- Liang Eric Yen · 1993 to 2026
$9.2MTraining in Cellular & Molecular Mechanisms of Tumor RejectionT32CA082084 · NCI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Robert J Binder, Dario AA Vignali · 1999 to 2026
$9.2MCentral metabolism of Salmonella in the inflamed gutR01AI118807 · NIAID · UT SOUTHWESTERN MEDICAL CENTER · PI Sebastian E Winter · 2015 to 2026
$5.3MDetermining the contribution of microbial-derived metabolites to protective immunity in obesity-driven cancer risk.U01CA272541 · NCI · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · PI Liza Makowski-Hayes, Joseph F PIERRE · 2022 to 2026
$5.1MRole of microbial-modulated bile acid receptor signaling in breast cancerR01CA253329 · NCI · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · PI Katherine Loree Cook, Liza Makowski-Hayes · 2020 to 2026
$3.0MLinking steady-state cytokine signaling to alveolar macrophage function in homeostasis and lung infectionR01HL162658 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI GOTTSCHALK, RACHEL A · 2022 to 2025
$2.4MUsing three-dimensional protein networks to uncover immuno-modulatory molecular phenotypes in infectious diseaseDP2AI164325 · NIAID · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI DAS, JISHNU · 2021 to 2025
$2.4MTherapy with fecal microbiota transplantation and immune checkpoint blockade for solid tumorsU01CA268806 · NCI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI HASSANE M ZAROUR · 2022 to 2026
$2.4MRole of gut protists in celiac diseaseR01AI168478 · NIAID · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Reinhard Hinterleitner · 2023 to 2026
$2.3MNCI NIH HHS F31 CA290756NCI NIH HHS F32 CA284780NCI NIH HHS P30 CA047904NCI NIH HHS P50 CA254865NCI NIH HHS R01 CA253329NCI NIH HHS R01 CA293654NCI NIH HHS R21 CA259636NCI NIH HHS T32 CA082084NCI NIH HHS U01 CA268806NCI NIH HHS U01 CA272541NHLBI NIH HHS R01 HL160747NHLBI NIH HHS R01 HL162658NIAID NIH HHS DP2 AI164325NIAID NIH HHS R01 AI118807NIAID NIH HHS R01 AI168478NIAID NIH HHS R21 AI163721NIAID NIH HHS R21 AI188307NIDDK NIH HHS R01 DK130897NIDDK NIH HHS R01 DK138912NIDDK NIH HHS T32 DK007665NIGMS NIH HHS P20 GM103418NIH HHS S10 OD023402NIH HHS S10 OD032141
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.
Indexed as
CD8-Positive T-LymphocytesGastrointestinal MicrobiomeImmunotherapyMelanomaPhysical Conditioning, AnimalAnimalsCell Line, TumorFemaleFormatesHumansImmune Checkpoint InhibitorsMiceMice, Inbred C57BLFormatesformic acidImmune Checkpoint InhibitorsCD8 T cellsexerciseFMTformateimmune checkpoint inhibitormelanomamicrobiotamicrobiota metaboliteNrf2
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.