Taken together, our study demonstrates that targeting nNOS-NO signaling using nNOS-selective inhibitors may be an effective strategy for melanoma treatment, given its novel mechanism of action, not only inhibiting nNOS-stimulated melanoma progression by reducing the production of NO, but also by inhibiting IFN-γ-activated STAT1/3 and PD-L1. Here, NOS1 is linked to melanoma.