S-nitrosylation topology in melanoma: established mechanisms, unresolved redox-immune links, and a testable framework.

Melanoma therapies can produce substantial tumor regression without durable control, raising two separable questions: how efficiently tumor cells are eliminated and whether therapy-induced death supports immune recognition. This review examines whether melanocytic-lineage redox biology and site-selective protein S-nitrosylation help connect these outcomes. We distinguish mechanisms demonstrated directly in melanoma from mechanistic precedents in other systems and from hypotheses that require validation. In melanocytic cells, active pigment-forming chemistry can support a nitric oxide synthase (NOS)-active state. In melanoma, S-nitrosylation has been linked to MAPK persistence during MEK inhibition, TSC2-dependent mTOR activation, and NOS1-dependent suppression of interferon programs through HDAC2 and IRF7. Pharmacological S-nitrosylation blockade also increases ER stress signaling, calreticulin exposure, HMGB1 release, immune cell recruitment, and tumor control, but these observations do not establish a site-specific effect on the immunological quality of cell death. We therefore propose a two-gate framework in which S-nitrosylation may regulate both susceptibility to irreversible death and the signaling competence of dying cells. Establishing this model will require quantitative site occupancy, cell type-resolved nitrosoproteomics, causal site replacement, and immune assays that distinguish altered signaling from simply increased cell killing. The available evidence supports selective interrogation of causal S-nitrosylation nodes rather than indiscriminate suppression of NO biology.