S-nitrosylation topology in melanoma: established mechanisms, unresolved redox-immune links, and a testable framework
- 1Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- 2Corresponding author.
Abstract
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.
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BibTeX
@article{srivastava2026snitrosylation,
title = {{S-nitrosylation topology in melanoma: established mechanisms, unresolved redox-immune links, and a testable framework}},
author = {Jyoti Srivastava and Sanjay Premi},
journal = {Redox Biology},
year = {2026},
month = oct,
doi = {10.1016/j.redox.2026.104401},
url = {https://doi.org/10.1016/j.redox.2026.104401},
note = {CC BY},
}
RIS
TY - JOUR
TI - S-nitrosylation topology in melanoma: established mechanisms, unresolved redox-immune links, and a testable framework
AU - Jyoti Srivastava
AU - Sanjay Premi
PY - 2026
DA - 2026/10/30
JO - Redox Biology
DO - 10.1016/j.redox.2026.104401
UR - https://doi.org/10.1016/j.redox.2026.104401
AB - 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.
SN - 2213-2317
ER -