By studying various tumor models exhibiting phenotypic traits of reduced, early or late resistance to a therapeutic antibody inhibiting the PD-1 immune checkpoint, we have unraveled IFNAR-induced NOS2 expression as a critical negative regulator of sustained anti-cancer efficacy of the PD-1 blockade that operates at the level of both tumor cells and leukocytes. This evidence concerns the gene NOS2 and neoplasm.