Polymer‐PARPi Conjugates Delivering USP1i for Maximizing Synthetic Lethality to Stimulate STING Pathway in High‐Grade Serous Ovarian Cancer

Abstract Overcoming the immunosuppressive tumor microenvironment and therapeutic resistance remains a significant challenge in ovarian cancer treatment. In this study, a glutathione‐responsive polymeric nanoparticle platform for the co‐delivery of the USP1 inhibitor SJB3‐019A and the PARP inhibitor Niraparib is developed. This system synergistically enhances DNA damage accumulation, suppresses homologous recombination repair, and robustly activate the STING signaling pathway, leading to enhanced type I interferon responses and mitigation of immune evasion. Mechanistically, USP1 inhibition significantly impairs DNA repair, amplifying the synthetic lethality of PARP inhibition and promoting immunogenic cell death. In vivo studies demonstrated precise, glutathione‐responsive drug release and substantial tumor accumulation of the nanoparticles, resulting in remarkable antitumor efficacy in murine ovarian cancer models. Importantly, this combinational approach effectively remodels the tumor microenvironment by increasing CD8⁺ T cell infiltration and enhancing tumor sensitivity to immune checkpoint blockade therapies. This innovative strategy targeting DNA damage responses presents a promising platform for precise and effective ovarian cancer immunotherapy.