NNMT and the methylation sink: integrating metabolism, epigenetics and immunity in cancer

Nicotinamide N-methyltransferase (NNMT) is a methyltransferase that uses S-adenosyl-L-methionine (SAM, cofactor) to catalyze the N-methylation of nicotinamide (NAM, substrate), yielding 1-methylnicotinamide (MNAM) and S-adenosyl-homocysteine (SAH). By consuming SAM and generating SAH, NNMT establishes a cellular "methylation sink" that couples metabolic reprogramming to epigenetic remodeling across DNA, RNA and proteins. Accumulating evidence shows that NNMT is upregulated in multiple malignancies, across both cancer cells and stromal lineages such as cancer-associated fibroblasts and pericytes. Its activity correlates with key hallmarks of cancer progression, including tumor growth, metastasis potential, metabolic rewiring, immune evasion, angiogenesis, maintenance of stem-like states, and resistance to therapy (including chemotherapy, targeted agents, and radiotherapy). These properties nominate NNMT as a candidate biomarker for diagnosis and stratification and as a tractable therapeutic node. We synthesize current knowledge of NNMT-driven cellular and microenvironmental mechanisms in tumorigenesis and progression, and summarize emerging therapeutic strategies, which include competitive inhibitors targeting the substrate or cofactor binding sites, microenvironment-activated prodrugs, and rational combinations with immune checkpoint blockade and targeted therapy to provide a conceptual and translational framework for developing NNMT-directed interventions.