Here we demonstrated that despite a low mutational rate in GC, GOF MADCAM1 mutations could play driver roles in promoting tumor metastasis through establishing immunosuppressive microenvironment, and MADCAM1MUT-reprogrammed-TAMs and Akt/mTOR signaling pathway may contribute to resistance to anti-PD-1/PD-L1 therapy. This evidence concerns the gene MADCAM1 and neoplasm.