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. Overall design: Single nuclei RNA-sequencing of omental metastases of seven chemotherapy-naïve high-grade serous ovarian cancer (HGSOC) patients.