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NNMT inhibition in cancer-associated fibroblasts restores antitumour immunity

Author

Listed:
  • Janna Heide

    (University of Chicago)

  • Agnes J. Bilecz

    (University of Chicago)

  • Samarjit Patnaik

    (National Institutes of Health)

  • Maria Francesca Allega

    (University of Chicago)

  • Leonhard Donle

    (University of Chicago)

  • Kaiting Yang

    (University of Chicago)

  • Ethan Teich

    (University of Chicago)

  • Yan Li

    (University of Chicago)

  • Qiaoshan Lin

    (University of Chicago)

  • Ke Kong

    (National Institutes of Health)

  • Li Liu

    (National Institutes of Health)

  • Tae Gyun Yang

    (National Institutes of Health)

  • Ken Chih-Chien Cheng

    (National Institutes of Health)

  • Jonathan H. Shrimp

    (National Institutes of Health)

  • Quinlin M. Hanson

    (National Institutes of Health)

  • Min Shen

    (National Institutes of Health)

  • Hongmao Sun

    (National Institutes of Health)

  • Hardik Shah

    (University of Chicago)

  • Lisa Schweizer

    (University of Chicago
    Max Planck Institute of Biochemistry)

  • Katarzyna Zawieracz

    (University of Chicago
    University of Chicago)

  • Andrea Olland

    (Schrödinger Framingham)

  • Andre White

    (Schrödinger Framingham)

  • Robert K. Suto

    (Schrödinger Framingham)

  • Razzaq Alhunayan

    (University of Chicago)

  • Medine Taşdemir

    (University of Chicago)

  • Noa Longman

    (University of Chicago)

  • Hua Liang

    (University of Chicago)

  • Matthias Mann

    (Max Planck Institute of Biochemistry)

  • Gordon M. Stott

    (Frederick National Laboratory for Cancer Research)

  • Matthew D. Hall

    (National Institutes of Health)

  • Simon Schwörer

    (University of Chicago)

  • Ralph R. Weichselbaum

    (University of Chicago)

  • András Piffkó

    (University of Chicago)

  • Ernst Lengyel

    (University of Chicago)

Abstract

Cancer-associated fibroblasts (CAFs) have a pivotal cancer-supportive role, yet CAF-targeted therapies are lacking1,2. Here, using spatial transcriptomics and single-cell RNA sequencing, we investigate the role of nicotinamide N-methyltransferase (NNMT) in high-grade serous ovarian cancer. Mechanistically, NNMT-induced H3K27me3 hypomethylation drives complement secretion from CAFs, attracting immunosuppressive myeloid-derived suppressor cells (MDSCs) to the tumour. Nnmt knockout in immunocompetent mice impairs tumour growth in syngeneic ovarian, breast and colon tumour models through enhanced CD8+ T cell activation. Using high-throughput screening, we develop a potent and specific NNMT inhibitor that reduces the tumour burden and metastasis in multiple mouse cancer models and restores immune checkpoint blockade efficacy by decreasing CAF-mediated recruitment of MDSCs and reinvigorating CD8+ T cell activation. Our findings establish NNMT as a central CAF regulator and a promising therapeutic target to mitigate immunosuppression in the tumour microenvironment.

Suggested Citation

  • Janna Heide & Agnes J. Bilecz & Samarjit Patnaik & Maria Francesca Allega & Leonhard Donle & Kaiting Yang & Ethan Teich & Yan Li & Qiaoshan Lin & Ke Kong & Li Liu & Tae Gyun Yang & Ken Chih-Chien Chen, 2025. "NNMT inhibition in cancer-associated fibroblasts restores antitumour immunity," Nature, Nature, vol. 645(8082), pages 1051-1059, September.
    • Handle: RePEc:nat:nature:v:645:y:2025:i:8082:d:10.1038_s41586-025-09303-5
    DOI: 10.1038/s41586-025-09303-5
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