2. Academic Validation
  3. NNMT inhibition in cancer-associated fibroblasts restores antitumour immunity

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

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. elengyel@uchicago.edu.
  • # 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.

Figures
Products