Interferon gamma (IFN-gamma) in the melanoma tumor microenvironment plays opposing roles, orchestrating both pro-tumorigenic activity and anticancer immune responses. Our previous studies demonstrated the role of neuronal nitric oxide synthase (nNOS) in IFN-gamma-stimulated melanoma progression. However, the underlying mechanism has not been well defined. Bioinformatic analysis of patient and cellular proteomic data was conducted to identify proteins of interest associated with IFN-gamma treatment in melanoma. Our omics analysis revealed that the induction of COX-2 was significantly predictive of IFN-gamma treatment in melanoma cells. In the presence of IFN-gamma, PGE 2 further enhanced PD-L1 expression and amplified the induction of nNOS, which increased intracellular NO levels. Cotreatment with celecoxib, a selective COX-2 inhibitor, effectively diminished these changes induced by PGE 2 . nNOS blockade using a selective small molecule inhibitor (HH044) efficiently inhibited IFN-gamma-Induced PGE 2 production and COX-2 expression in melanoma cells. STAT3 inhibitor napabucasin also inhibited COX-2 expression both in the presence and absence of IFN-gamma. In vivo , HH044 treatment significantly reduced tumor PGE 2 levels in a human melanoma xenograft mouse model (A375/Nu/Nu). Combination treatment with HH044 and celecoxib yielded the greatest tumor suppression in the syngeneic murine melanoma model (Cloudman S91/DBA/2), reducing tumor volume to 19% of control, compared to 38% and 52% with HH044 or celecoxib alone, respectively. Furthermore, transcriptomic analysis revealed significant changes in genes involved in matrix remodeling and metastasis after HH044 treatment. Ex vivo co-culturing human PBMCs with melanoma cells inhibited T cell activation, decreasing IL-2-secreting T cells in the presence and absence of IFN-gamma. PBMCs from a significant portion of donors (64%) were reactivated by HH044 pretreatment, displaying a significant increase in IL-2+ T cells after coincubation with melanoma cells.Our study reveals a positive feedback loop linking nNOS-mediated NO signaling to the COX-2/PGE 2 signaling axis in melanoma, thereby further enhancing the pro-tumorigenic activity of IFN-gamma. Disrupting crosstalk between nNOS/NO and COX-2 with selective inhibitors effectively suppressed melanoma tumor growth, possibly by modulating the tumor immune microenvironment.