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NNMT inhibition in cancer-associated fibroblasts restores antitumor immunity

GSE292661 Homo sapiens Expression profiling by high throughput sequencing 7 samples Submitted 2025/05/09 Platform GPL24676
Summary
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.
Published in
NNMT inhibition in cancer-associated fibroblasts restores antitumour immunity
Heide J, Bilecz AJ, Patnaik S et al. · Nature 2025 · PMID 40702186 · doi:10.1038/s41586-025-09303-5
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Also filed as BioProject PRJNA1240623 and SRA study SRP572348. Searching any of these in the dataset finder brings you back here.

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