近日，美国芝加哥大学教授Ernst Lengyel及其小组的研究发现抑制癌症相关成纤维细胞中的NNMT可恢复抗肿瘤免疫。该研究于2025年7月23日发表于国际一流学术期刊《自然》杂志上。

以空间转录组学和单细胞RNA测序为主题，课题组研究了烟酰胺N-甲基转移酶（NNMT）在高级别血清性卵巢癌中的作用。从机制上讲，NNMT诱导的H3K27me3低甲基化驱动CAFs的补体分泌，吸引免疫抑制性髓源性抑制细胞（MDSCs）进入肿瘤。在免疫功能正常小鼠中敲除Nnmt可通过增强CD8⁺ T细胞激活，损害同基因卵巢、乳腺和结肠肿瘤模型的肿瘤生长。

通过高通量筛选，研究团队开发了一种有效的特异性NNMT抑制剂，可以减少多主题癌症模型中的肿瘤负担和转移，并通过减少CAF介导的MDSCs募集和重新激活CD8⁺ T细胞激活来恢复免疫检查点阻断的功效。他们的发现确立了NNMT作为中心CAF调节剂和缓解肿瘤微环境中免疫抑制的有希望的治疗靶点。

据介绍，癌症相关成纤维细胞（CAFs）具有关键的癌症支持作用，但CAFs靶向治疗缺乏。

附：英文原文

Title: NNMT inhibition in cancer-associated fibroblasts restores antitumour immunity

Author: 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, Tademir, Medine, Longman, Noa, Liang, Hua, Mann, Matthias, Stott, Gordon M., Hall, Matthew D., Schwrer, Simon, Weichselbaum, Ralph R., Piffk, Andrs, Lengyel, Ernst

Issue&Volume: 2025-07-23

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.

DOI: 10.1038/s41586-025-09303-5

Source: https://www.nature.com/articles/s41586-025-09303-5