Skip to content
DraconiticResearch
Search Sources API
203,234 studies31 sourcesUpdated 16 min ago
Peer-reviewedCC BY-NC-ND 4.0Nature Immunology

Compartment-specific PPARδ activity controls the outcome of cancer–immune cell competition and immunotherapy efficacy

  • Paul Bunk1
  • Ilgin Ergin1
  • Timothy Maher1,2,3
  • Vyom Shah1,4
  • Julia R. Bonney5
  • Lokesh B. S. S. Kumar1
  • Charlie Chung1,2
  • Nils Wellhausen6
  • Philip Moresco1,2,3
  • Sarah Shao1
  • Jill Habel1
  • Vinay Mandati1
9 more authors
  • Rachel Rubino1
  • David E. Rivadeneira7,8
  • John E. Wilkinson9
  • Laura Herrero10,11,12
  • Peter M. K. Westcott1
  • Samuel E. Weinberg13
  • Saar I. Gill6,14
  • Nathalie Y. R. Agar5,15,16
  • Semir Beyaz1
16 affiliations
  1. 1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY USA
  2. 2Graduate Program in Genetics, Stony Brook University, Stony Brook, NY USA
  3. 3Medical Scientist Training Program, Stony Brook University Renaissance School of Medicine, Stony Brook University, Stony Brook, NY USA
  4. 4Rutgers New Jersey Medical School, New Jersey, USA
  5. 5Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA
  6. 6Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA
  7. 7Department of Surgery, Donald and Barbara Zucker School of Medicine Hofstra University, Northwell Health, Hempstead, NY USA
  8. 8Colorectal Surgery and Surgical Services, Huntington Hospital, Huntington, NY USA
  9. 9University of Michigan-Ann Arbor, Ann Arbor, MI USA
  10. 10Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Universitat de Barcelona, Barcelona, Spain
  11. 11Institute of Biomedicine of the University of Barcelona (IBUB), Universitat de Barcelona, Barcelona, Spain
  12. 12Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
  13. 13Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL USA
  14. 14Parker Institute for Cancer Immunotherapy at University of Pennsylvania, University of Pennsylvania, Philadelphia, PA USA
  15. 15Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA
  16. 16Department of Cancer Biology, Dana-Farber Cancer Institute; Harvard Medical School, Boston, MA USA
Read full textDOICite

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.

Related

  1. Compartment-Specific Transcriptional Remodelling Defines Denervation and Geriatric Muscle Regeneration
    Wanting Tong, Qi Yu, Renyu Yang +3
    International Journal of Molecular SciencesPeer-reviewedCC BY 4.0Molecular biology & gene regulationCrossref
  2. Compartment-Specific Amino Acid Dysregulation in Depression: Integrating Non-Targeted Metabolomics with Brain Barrier Biology
    Ivana Perić, Andrijana Stanisavljević Ilić, Neda Đorđević +1
    International Journal of Molecular SciencesPeer-reviewedCC BY 4.0General biochemistryCrossref
  3. Compartment-specific m7G RNA modification in cancer: mechanisms, tumor adaptation, and therapeutic vulnerabilities
    Xiaoxiao Tian, Di Huang, Chaonan Guan
    Frontiers in Molecular BiosciencesPeer-reviewedCC BY 4.0Molecular biology & gene regulationFrontiers
  4. Compartment-specific cAMP dysfunction in diabetic cardiomyopathy in hiPSC-derived cardiomyocytes: therapeutic potential of fibroblast growth factor 1
    Kun Liu, Kazuki Osuka, Mengying Xu +21
    Cardiovascular DiabetologyPeer-reviewedCC BY 4.0Full textMolecular biology & gene regulationPMC
  5. 1017 Computational design of de novo antigen-specific T cell receptors using AI optimization and long-time-scale molecular simulations for targeted cancer immunotherapy
    Kellie N Smith, Yash Bhargava, Samuel J Huang +1
    Journal for ImmunoTherapy of CancerPeer-reviewedCC BYMolecular biology & gene regulationDOAJ

Cite

BibTeXRIS
BibTeX
@article{bunk2026compartmentspecific,
  title = {{Compartment-specific PPARδ activity controls the outcome of cancer–immune cell competition and immunotherapy efficacy}},
  author = {Paul Bunk and Ilgin Ergin and Timothy Maher and Vyom Shah and Julia R. Bonney and Lokesh B. S. S. Kumar and Charlie Chung and Nils Wellhausen and Philip Moresco and Sarah Shao and Jill Habel and Vinay Mandati and Rachel Rubino and David E. Rivadeneira and John E. Wilkinson and Laura Herrero and Peter M. K. Westcott and Samuel E. Weinberg and Saar I. Gill and Nathalie Y. R. Agar and Semir Beyaz},
  journal = {Nature Immunology},
  year = {2026},
  month = oct,
  doi = {10.1038/s41590-026-02685-2},
  url = {https://doi.org/10.1038/s41590-026-02685-2},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Compartment-specific PPARδ activity controls the outcome of cancer–immune cell competition and immunotherapy efficacy
AU  - Paul Bunk
AU  - Ilgin Ergin
AU  - Timothy Maher
AU  - Vyom Shah
AU  - Julia R. Bonney
AU  - Lokesh B. S. S. Kumar
AU  - Charlie Chung
AU  - Nils Wellhausen
AU  - Philip Moresco
AU  - Sarah Shao
AU  - Jill Habel
AU  - Vinay Mandati
AU  - Rachel Rubino
AU  - David E. Rivadeneira
AU  - John E. Wilkinson
AU  - Laura Herrero
AU  - Peter M. K. Westcott
AU  - Samuel E. Weinberg
AU  - Saar I. Gill
AU  - Nathalie Y. R. Agar
AU  - Semir Beyaz
PY  - 2026
DA  - 2026/10/14
JO  - Nature Immunology
DO  - 10.1038/s41590-026-02685-2
UR  - https://doi.org/10.1038/s41590-026-02685-2
AB  - 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.
SN  - 1529-2908
SN  - 1529-2916
ER  -