{
  "abstract": "Most patients with solid tumors fail to sustain antitumor immunity, in part because immune cells cannot outcompete cancer cells inside the immunosuppressive tumor microenvironment. Here, we show the lipid-sensing transcription factor PPARδ is a compartment-specific determinant of cancer–immune fitness balance and immunotherapy efficacy. Activating PPARδ in cancer cells promotes their growth and impairs antitumor immunity, whereas activating it in immune cells drives tumor suppression and overrides tumor-promoting effects of cancer-intrinsic activation. Mechanistically, PPARδ enhances CD8+ T cell fitness against cancer through effector-associated chromatin remodeling and Cpt1a-mediated fatty acid oxidation. Therapeutically, PPARδ-activated CD8+ T cells sensitize immunotherapy-resistant microsatellite stable metastatic colorectal cancer to checkpoint blockade in mice, and pharmacological or genetic PPARδ activation enhances human chimeric antigen receptor T cell function. These findings identify compartment-specific PPARδ activity as a targetable driver of immune cell fitness that can be harnessed to improve outcomes in immunotherapy-resistant tumors.",
  "abstract_shown": true,
  "affiliations": [
    "Cold Spring Harbor Laboratory, Cold Spring Harbor, NY USA",
    "Graduate Program in Genetics, Stony Brook University, Stony Brook, NY USA",
    "Medical Scientist Training Program, Stony Brook University Renaissance School of Medicine, Stony Brook University, Stony Brook, NY USA",
    "Rutgers New Jersey Medical School, New Jersey, USA",
    "Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA",
    "Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA",
    "Department of Surgery, Donald and Barbara Zucker School of Medicine Hofstra University, Northwell Health, Hempstead, NY USA",
    "Colorectal Surgery and Surgical Services, Huntington Hospital, Huntington, NY USA",
    "University of Michigan-Ann Arbor, Ann Arbor, MI USA",
    "Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Universitat de Barcelona, Barcelona, Spain",
    "Institute of Biomedicine of the University of Barcelona (IBUB), Universitat de Barcelona, Barcelona, Spain",
    "Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain",
    "Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL USA",
    "Parker Institute for Cancer Immunotherapy at University of Pennsylvania, University of Pennsylvania, Philadelphia, PA USA",
    "Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA",
    "Department of Cancer Biology, Dana-Farber Cancer Institute; Harvard Medical School, Boston, MA USA"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 21,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Paul Bunk",
      "orcid": "0000-0003-3564-7165"
    },
    {
      "affs": [
        0
      ],
      "name": "Ilgin Ergin",
      "orcid": "0000-0002-0007-6502"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Timothy Maher"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Vyom Shah",
      "orcid": "0000-0001-6874-5285"
    },
    {
      "affs": [
        4
      ],
      "name": "Julia R. Bonney"
    },
    {
      "affs": [
        0
      ],
      "name": "Lokesh B. S. S. Kumar"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Charlie Chung"
    },
    {
      "affs": [
        5
      ],
      "name": "Nils Wellhausen"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Philip Moresco"
    },
    {
      "affs": [
        0
      ],
      "name": "Sarah Shao",
      "orcid": "0009-0004-4432-4098"
    },
    {
      "affs": [
        0
      ],
      "name": "Jill Habel"
    },
    {
      "affs": [
        0
      ],
      "name": "Vinay Mandati"
    },
    {
      "affs": [
        0
      ],
      "name": "Rachel Rubino"
    },
    {
      "affs": [
        6,
        7
      ],
      "name": "David E. Rivadeneira"
    },
    {
      "affs": [
        8
      ],
      "name": "John E. Wilkinson"
    },
    {
      "affs": [
        9,
        10,
        11
      ],
      "name": "Laura Herrero",
      "orcid": "0000-0003-4244-4673"
    },
    {
      "affs": [
        0
      ],
      "name": "Peter M. K. Westcott"
    },
    {
      "affs": [
        12
      ],
      "name": "Samuel E. Weinberg",
      "orcid": "0000-0002-9532-7051"
    },
    {
      "affs": [
        5,
        13
      ],
      "name": "Saar I. Gill"
    },
    {
      "affs": [
        4,
        14,
        15
      ],
      "name": "Nathalie Y. R. Agar"
    },
    {
      "affs": [
        0
      ],
      "name": "Semir Beyaz",
      "orcid": "0000-0003-4730-4012"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/bnwaxzayxv07c.bib",
  "cited_by": 0,
  "doi": "10.1038/s41590-026-02685-2",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13710178/",
  "id": "bnwaxzayxv07c",
  "issns": [
    "1529-2908",
    "1529-2916"
  ],
  "landing_url": "https://doi.org/10.1038/s41590-026-02685-2",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
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      "Article"
    ],
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      "openalex",
      "1312|Peroxisome Proliferator-Activated Receptors"
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  "openalex": "W7221805344",
  "pdf_url": null,
  "pmcid": "PMC13710178",
  "pmid": "42875546",
  "published": "2026-10-14",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/bnwaxzayxv07c.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T12:21:11Z",
      "native_id": "PMC13710178",
      "source": "pmc",
      "url": "https://doi.org/10.1038/s41590-026-02685-2"
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  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Peroxisome Proliferator-Activated Receptors",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Compartment-specific PPARδ activity controls the outcome of cancer–immune cell competition and immunotherapy efficacy",
  "title_text": "Compartment-specific PPARδ activity controls the outcome of cancer–immune cell competition and immunotherapy efficacy",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:21:11Z",
  "url": "https://research.draconitic.com/paper/bnwaxzayxv07c",
  "venue": "Nature Immunology",
  "versions": []
}