Stimulator of Interferon Genes (STING) Agonist-Loaded Copper-Based Nanoparticles for B7-H3 Blockade-Enhanced Chemodynamic-Immunotherapy of Ovarian Cancer
Abstract
Introduction Ovarian cancer remains difficult to treat because of limited tumor immunogenicity, poor cytotoxic T-cell infiltration, and a strongly immunosuppressive tumor microenvironment. Methods Characterization, in vitro cell experiments, and tumor mouse model was performed. Results Here, we developed an anti-B7-H3 antibody-modified, STING agonist-loaded copper-based nanoplatform for tumor-targeted chemodynamic-immunotherapy. The copper-containing nanoparticles enabled efficient loading of the non-nucleotide STING agonist MSA-2 and exhibited acid-responsive release of both MSA-2 and copper ions. Reactive oxygen species generation and intracellular glutathione depletion amplify oxidative stress, induce tumor-selective cytotoxicity, and trigger immunogenic cell death, as evidenced by increased release of ATP and HMGB1. Surface conjugation with anti-B7-H3 antibody preserved B7-H3-blocking activity and enhanced nanoparticle uptake, intracellular copper delivery, tumor accumulation in ovarian cancer cells. In vivo, the nanoplatform produced the strongest tumor-growth inhibition and significantly prolonged survival compared with non-targeted or single-component formulations. MSA-2 delivery was associated with enhanced STING pathway activation, increased inflammatory cytokine production, and improved antitumor immune responses, while anti-B7-H3 antibody modification promoted tumor accumulation. Importantly, the nanoplatform showed favorable biocompatibility, with no evident body-weight loss, major-organ injury, hematological abnormalities, or hepatic and renal dysfunction. Conclusion This multifunctional nanoplatform integrates B7-H3-mediated tumor targeting and immune blockade, copper-based chemodynamic therapy, immunogenic cell death, and STING activation, providing a promising strategy for remodeling the ovarian tumor immune microenvironment and enhancing systemic antitumor immunity.