m6A demethylation of NNMT in CAFs promotes gastric cancer progression by enhancing macrophage M2 polarization

Cancer associated fibroblasts (CAFs) are the predominant stromal cells in the tumor microenvironment of gastric cancer (GC), interacting with both immune and tumor cells to drive cancer progression. However, the precise link between these interactions and their potential as therapeutic targets remains poorly understood. In this study, we identified for the first time that nicotinamide N-methyltransferase (NNMT) derived from CAFs promoted M2 macrophage polarization, which, in turn, facilitated the proliferation and migration of GC cells. Additionally, we discovered that NNMT expression in CAFs was regulated by the Fat mass and obesity related protein (FTO) via m6A demethylation. Both NNMT and FTO were highly expressed in tumor tissues and CAFs, with a positive correlation between FTO and NNMT levels in clinical samples. Mechanistically, FTO bound to NNMT mRNA, reducing m6A modification and enhancing NNMT expression. Knockdown of either NNMT or FTO in CAFs effectively inhibited M2 macrophage polarization and suppressed GC progression. These findings were validated in patient-derived organoid models and nude mouse models of GC. Collectively, our data revealed that FTO promoted M2 macrophage polarization by regulating the m6A demethylation of NNMT in CAFs, thereby driving GC progression. This identified a potential novel target for GC diagnosis and therapy. •The FTO/NNMT axis in CAFs promotes macrophage M2 polarization and gastric cancer.•FTO and NNMT were upregulated in tumors and CAFs, with FTO positively correlating with NNMT.•FTO decreased NNMT m6A modification, boosting NNMT mRNA and protein expression.•FTO promotes macrophage M2 polarization by regulating NNMT m6A demethylation in CAFs.•Patient-derived organoids and nude mouse models are used to verify our hypothesis.