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

Area of Science:

• Biomedical Engineering
• Cancer Immunology
• Metabolic Reprogramming

Background:

• Tumor cells reprogram metabolism to create an immunosuppressive tumor microenvironment (TME), evading immune surveillance.
• Targeting tumor cell metabolism offers a potential strategy for TME immunomodulation and enhancing immunotherapy.

Purpose of the Study:

• To develop a tumor-specific peroxynitrite nanogenerator (APAP-P-NO) to disrupt metabolic homeostasis in melanoma cells.
• To investigate the mechanism of peroxynitrite-induced metabolic alterations and their impact on the TME.

Main Methods:

• Construction of a tumor-specific peroxynitrite nanogenerator (APAP-P-NO).
• Stimulation of APAP-P-NO by melanoma-specific conditions (acid, glutathione, tyrosinase) to generate peroxynitrite.
• Metabolomics profiling to analyze metabolic changes in tumor cells.
• Assessment of immune cell populations and T cell infiltration within the TME.
• Combination therapy with anti-PD-L1 in melanoma models.

Main Results:

• APAP-P-NO selectively disrupted metabolic homeostasis in melanoma cells by generating peroxynitrite.
• Peroxynitrite accumulation significantly decreased tricarboxylic acid cycle metabolites and glycolysis-derived lactate.
• Peroxynitrite impaired glyceraldehyde-3-phosphate dehydrogenase activity via S-nitrosylation, affecting glucose metabolism.
• Metabolic reprogramming reversed the immunosuppressive TME, promoting M1 macrophage polarization, reducing suppressive immune cells, and increasing CD8+ T cell infiltration.
• Combination of APAP-P-NO with anti-PD-L1 demonstrated significant inhibition of primary and metastatic melanomas with no systemic toxicity.

Conclusions:

• A novel tumor-specific peroxynitrite overproduction strategy was developed for TME immunomodulation.
• Peroxynitrite-mediated disruption of tumor cell metabolism effectively reverses the immunosuppressive TME.
• This approach shows promise for enhancing immunotherapy sensitivity in melanoma treatment.