NNMT inhibition in cancer-associated fibroblasts restores antitumour immunity

  • Nature. 2025 Jul 23. doi: 10.1038/s41586-025-09303-5.
Janna Heide  1 ,  Agnes J Bilecz  #  1 ,  Samarjit Patnaik  #  2 ,  Maria Francesca Allega  #  1 ,  Leonhard Donle  1 ,  Kaiting Yang  3 ,  Ethan Teich  1 ,  Yan Li  4 ,  Qiaoshan Lin  4 ,  Ke Kong  2 ,  Li Liu  2 ,  Tae Gyun Yang  2 ,  Ken Chih-Chien Cheng  2 ,  Jonathan H Shrimp  2 ,  Quinlin M Hanson  2 ,  Min Shen  2 ,  Hongmao Sun  2 ,  Hardik Shah  5 ,  Lisa Schweizer  1  6 ,  Katarzyna Zawieracz  1  7 ,  Andrea Olland  8 ,  Andre White  8 ,  Robert K Suto  8 ,  Razzaq Alhunayan  1 ,  Medine Taşdemir  1 ,  Noa Longman  1 ,  Hua Liang  3 ,  Matthias Mann  6 ,  Gordon M Stott  9 ,  Matthew D Hall  2 ,  Simon Schwörer  10 ,  Ralph R Weichselbaum  3 ,  András Piffkó  3 ,  Ernst Lengyel  11
Affiliations
  • 1. Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Chicago, Chicago, IL, USA.
  • 2. National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
  • 3. Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL, USA.
  • 4. Center for Research Informatics, University of Chicago, Chicago, IL, USA.
  • 5. Metabolomics Platform, Comprehensive Cancer Center, University of Chicago, Chicago, IL, USA.
  • 6. Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany.
  • 7. Department of Pathology, University of Chicago, Chicago, IL, USA.
  • 8. Schrödinger Framingham, Framingham, MA, USA.
  • 9. Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • 10. Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
  • 11. Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Chicago, Chicago, IL, USA. [email protected].
  • # Contributed equally.
PMID: 40702186 DOI: 10.1038/s41586-025-09303-5
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.

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