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, Taşdemir Medine, Longman Noa, Liang Hua, Mann Matthias, Stott Gordon M, Hall Matthew D, Schwörer Simon, Weichselbaum Ralph R, Piffkó András, Lengyel Ernst
Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Chicago, Chicago, IL, USA.
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Nature. 2025 Jul 23. doi: 10.1038/s41586-025-09303-5.
Cancer-associated fibroblasts (CAFs) have a pivotal cancer-supportive role, yet CAF-targeted therapies are lacking. 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.
癌症相关成纤维细胞（CAFs）在支持癌症发展方面起着关键作用，但针对CAFs的疗法却很匮乏。在此，我们运用空间转录组学和单细胞RNA测序技术，研究烟酰胺N-甲基转移酶（NNMT）在高级别浆液性卵巢癌中的作用。从机制上来说，NNMT诱导的H3K27me3低甲基化促使CAFs分泌补体，吸引免疫抑制性髓源性抑制细胞（MDSCs）至肿瘤部位。在具有免疫活性的小鼠中敲除Nnmt基因，可通过增强CD8 T细胞活化，在同基因卵巢癌、乳腺癌和结肠癌模型中抑制肿瘤生长。通过高通量筛选，我们研发出一种强效且特异性的NNMT抑制剂，该抑制剂可减轻多种小鼠癌症模型中的肿瘤负担并减少转移，还可通过减少CAF介导的MDSCs募集以及恢复CD8 T细胞活化来恢复免疫检查点阻断疗效。我们的研究结果表明，NNMT是CAF的核心调节因子，也是减轻肿瘤微环境中免疫抑制的一个有前景的治疗靶点。
