NNMT inhibition in cancer-associated fibroblasts restores antitumour immunity

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 Cheng, Jonathan H. Shrimp, Quinlin M. Hanson, Min Shen, Hongmao Sun, Hardik Shah, Lisa Schweizer, Katarzyna Zawieracz, Andrea Olland, Andre White, Robert K. Suto, Razzaq Alhunayan, Medine Taşdemir, Noa Longman, Hua Liang, Matthias Mann, Gordon M. Stott, Matthew D. Hall, Simon Schwörer, Ralph R. Weichselbaum, András Piffkó and Ernst Lengyel ()
Additional contact information
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
Katarzyna Zawieracz: 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

Nature, 2025, vol. 645, issue 8082, 1051-1059

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-025-09303-5

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