Tumor-Specific Peroxynitrite Overproduction Disrupts Metabolic Homeostasis for Sensitizing Melanoma Immunotherapy.

Tumor cells elicit metabolic reprogramming to establish an immunosuppressive tumor microenvironment (TME) for escaping from immunosurveillance. Therefore, interrupting the metabolic adaption of tumor cells might be a promising strategy for TME immunomodulation, favoring immunotherapy. Herein, w e construct a tumor-specific ONOO nanogenerator (APAP-P-NO) that can selectively disrupt metabolic homeostasis in melanoma cells. Stimulated by melanoma-characteristic acid, glutathione, and tyrosinase, APAP-P-NO could efficiently generate ONOO through the in situ coupling of the produced O and released NO. Metabolomics profiling reveals that the accumulated ONOO induces great decrease of metabolites involved in the TCA cycle. Meanwhile, the aerobic glycolysis-produced lactate drops sharply both intracellularly and extracellularly under ONOO stress. Mechanistically, ONOO impairs the activity of glyceraldehyde-3-phosphate dehydrogenase in glucose metabolism through S-nitrosylation. The metabolic alterations effectively reverse the immunosuppressive TME to evoke potent antitumor immune responses, including polarization of M2-like macrophages to M1 phenotype, reduction of myeloid-derived suppressor cells and regulatory T cells, and restoration of CD8 T cell infiltration. Combining APAP-P-NO pretreatment with anti-PD-L1 achieves a significant inhibition against both primary and metastatic melanomas without systemic toxicities. Collectively, w e develop a tumor-specific ONOO overproduction approach and explore the possible mechanism of ONOO -mediated TME immunomodulation, providing a new strategy for facilitating immunotherapy sensitivity. This article is protected by copyright. All rights reserved.