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 was increased with tumor progression and correlated with tumor immune escape through inhibition on type I interferon (IFN) signaling. However, the immune regulatory role and its related mechanism of NOS1 and its impacts on immune therapy such as immune checkpoint blockade (ICB) in melanoma is unclear. Here, we found that NOS1 expression induced IRF7 modification by s-nitrosylation at C435 site in mouse (C481 in human), which functionally promotes tumor growth in mouse models. Mechanically, IRF7-C435-SNO inhibited IFNβ transcription under PRR signal activation, leading to disorder in initiation of type I interferons response in melanoma cell. In melanoma mouse model, IRF7-C435-SNO decreased infiltration and activation of CD8 T cells in tumor microenvironment, by reducing antigen presentation processes in tumor cells and inhibits the maturation of DC1. Clinically, high expression of NOS1 correlated with poor survival prognosis and resistance with to ICB anti-tumor therapies in melanoma cases with less immune cell infiltration. Our study suggested that NOS1 expression in melanoma characterizes IFN-I signal disorders in response to innate immune stimulation by IRF7 s-nitrosylation. Targeting NOS1 signaling might benefit for overcome of immune therapeutically resistance particularly in immune cold melanoma phenotype.