NNMT inhibition in cancer-associated fibroblasts restores antitumor immunity

Cancer-associated fibroblasts (CAFs) play a pivotal cancer-supportive role, yet CAF-targeted therapies remain elusive. Through spatial transcriptomics and single-cell RNA sequencing, we identified nicotinamide N-methyltransferase (NNMT) as a central CAF regulator in high-grade serous ovarian cancer (HGSOC) patients. Mechanistically, NNMT-induced H3K27me3 hypomethylation drives complement secretion from CAFs, attracting immunosuppressive myeloid-derived suppressor cells (MDSCs) to the tumor. Using high-throughput screening, we developed a potent, specific NNMT inhibitor that reduces tumor burden in multiple murine cancer models and restores immune checkpoint blockade efficacy by decreasing CAF-mediated MDSC recruitment and reinvigorating CD8⁺ T cell activation. Our findings establish NNMT as an essential CAF regulator and promising therapeutic target to mitigate immunosuppression in the tumor microenvironment. Single nuclei RNA-sequencing of omental metastases of seven chemotherapy-naïve high-grade serous ovarian cancer (HGSOC) patients.

癌相关成纤维细胞（Cancer-associated fibroblasts, CAFs）发挥关键的促肿瘤作用，但针对CAFs的靶向治疗仍未取得突破。本研究通过空间转录组学与单细胞RNA测序技术，在高级别浆液性卵巢癌（high-grade serous ovarian cancer, HGSOC）患者中鉴定出烟酰胺N-甲基转移酶（nicotinamide N-methyltransferase, NNMT）作为CAFs的核心调控因子。机制层面，NNMT介导的H3K27me3低甲基化可驱动CAFs分泌补体，将免疫抑制性髓系来源抑制细胞（myeloid-derived suppressor cells, MDSCs）招募至肿瘤微环境。本研究通过高通量筛选开发出一种强效且特异性的NNMT抑制剂，该抑制剂可在多种小鼠肿瘤模型中降低肿瘤负荷，并通过减少CAFs介导的MDSC招募、重振CD8阳性T细胞活化，恢复免疫检查点阻断治疗的疗效。本研究证实NNMT是CAFs的关键调控因子，亦是缓解肿瘤微环境免疫抑制的极具潜力的治疗靶点。本研究还对7例初治高级别浆液性卵巢癌患者的网膜转移灶开展了单细胞核RNA测序。