Abstract 2248: Inhibiting NNMT in cancer-associated fibroblasts reduces immunosuppression

Cancer-associated fibroblasts (CAFs) are critical in supporting cancer progression, yet effective CAF-targeted therapies are lacking. Through spatial transcriptomics and single-cell RNA sequencing, we identified nicotinamide N-methyltransferase (NNMT) upregulation and the resulting histone hypomethylation as a global regulator across various CAF subtypes. NNMT-expressing CAFs activate the complement system and recruit myeloid-derived suppressor cells (MDSCs), driving an immunosuppressive tumor microenvironment. Using high-throughput screening, we developed a potent NNMT inhibitor (NNMTi) that significantly reduces tumor burden in murine cancer models by decreasing MDSC infiltration and enhancing CD8+ T cell activation, thereby restoring the efficacy of immune checkpoint inhibitors. These findings establish NNMT as a key regulator of the CAF landscape and present a novel therapeutic strategy for reprogramming the tumor microenvironment. Citation Format: Janna Heide, Agnes J. Bilecz, Maria F. Allega, Samarjit Patnaik, Gordon M. Stott, Matthew D. Hall, Andras Piffko, Ernst Lengyel. Inhibiting NNMT in cancer-associated fibroblasts reduces immunosuppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2248.