NNMT inhibition in cancer-associated fibroblasts restores antitumour immunity

• 成果类型: Article
• 署名作者: Heide, Janna; Bilecz, Agnes J.; Patnaik, Samarjit; Allega, Maria Francesca; Donle, Leonhard; Yang, Kaiting; Teich, Ethan; Li, Yan; Lin, Qiaoshan; Kong, Ke; Liu, Li; Yang, Tae Gyun; Cheng, Ken Chih-Chien; Shrimp, Jonathan H.; Hanson, Quinlin M.; Shen, Min; Sun, Hongmao; Shah, Hardik; Schweizer, Lisa; Zawieracz, Katarzyna; Olland, Andrea; White, Andre; Suto, Robert K.; Alhunayan, Razzaq; Tasdemir, Medine; Longman, Noa; Liang, Hua; Mann, Matthias; Stott, Gordon M.; Hall, Matthew D.; Schworer, Simon; Weichselbaum, Ralph R.; Piffko, Andras; Lengyel, Ernst
• 署名单位: University of Chicago; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS); University of Chicago; University of Chicago; University of Chicago; University of Chicago; Robert H. Lurie Comprehensive Cancer Center; Max Planck Society; University of Chicago; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research; University of Chicago
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-09303-5
• 发表日期: 2025-09-25
• 关键词: nicotinamide n-methyltransferase; ovarian-cancer; in-vivo; microenvironment; DISCOVERY; models; tools

摘要

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.