Nicotinamide N-methyltransferase in tumor stroma–immune crosstalk: Metabolic–epigenetic mechanisms and translational opportunities
Year: 2026
Type: article
Abstract: ) salvage, and methyl-donor metabolism. Although NNMT has traditionally been studied as a tumor-cell enzyme and prognostic marker, accumulating evidence implicates compartment-specific activity in cancer-associated fibroblasts (CAFs) and stromal-immune remodeling. The literature spans different tumor types and experimental systems, however, and often conflates NNMT expression, pathway activity, and functional dependency. This review organizes NNMT biology by cellular source and mechanistic route. We distinguish tumor-cell-intrinsic programs from CAF-dependent matrix, vascular, secretory, and myeloid outputs; identify which links were tested within the same model; and specify where immune consequences remain incomplete or derive from cross-model integration. In malignant cells, NNMT can support plasticity, stem-like states, invasion, metabolic adaptation, and treatment-specific resistance. In CAFs, it can maintain selected fibroblast states and regulate extracellular matrix remodeling, mechanotransduction, angiogenic signaling, and inflammatory secretion. In selected models, 1-MNA directly modulates T-cell function, and defined CAF- or tumor-cell-initiated circuits alter myeloid populations and response to checkpoint blockade; several matrix, vascular, and cross-compartment links remain unresolved. NNMT is therefore better viewed as a context-dependent metabolic-epigenetic regulator than as a universal oncogenic switch or conserved linear CAF-myeloid-T-cell axis. Translation will require spatially resolved patient selection, validated pharmacodynamic biomarkers, selective cell-active interventions, and combinations matched to the dominant NNMT-dependent program.
Source: International Immunopharmacology
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,220
OpenAlex ID: W7213974807