S-nitrosylation of IRF7 induced by NOS1 expression in melanoma suppresses anti-tumor immunity.

Endogenous nitric oxide (NO) produced by nitric oxide synthases (NOSs) plays an important immunosuppressive role in the tumor microenvironment. In melanoma, NOS1 expression increases with tumor progression and correlates with tumor immune escape through the inhibition of type I interferon (IFN) signaling. However, the immune regulatory role and related mechanisms of NOS1, as well as its impacts on immune therapies such as immune checkpoint blockade (ICB) in melanoma, remain unclear. Here, we found that NOS1 expression induces IRF7 modification by S-nitrosylation at the C435 site in mice (C481 in humans), which functionally promoted tumor growth in mouse models. Mechanistically, IRF7-C435-SNO inhibited IFNβ transcription under PRR signal activation, leading to a disorder in the initiation of the type I interferon response in melanoma cells. In a melanoma mouse model, IRF7-C435-SNO decreased the infiltration and activation of CD8 + T cells in the tumor microenvironment by reducing antigen presentation processes in tumor cells and inhibiting the maturation of DC1. Clinically, high expression of NOS1 correlated with poor survival prognosis and resistance to ICB anti-tumor therapies in melanoma cases with less immune cell infiltration. Our study suggests that NOS1 expression in melanoma characterizes IFN-I signal disorders in response to innate immune stimulation through IRF7 s-nitrosylation. Targeting NOS1 signaling might be beneficial for overcoming immune therapeutically resistance, particularly in immune-cold melanoma phenotype.