LAUSR

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 O2 •- 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.