A nanosystem targeting genomic instability and mitochondrial damage to stimulate STING pathway for synergistic immunotherapy for advanced prostate cancer.

Taxane-based chemotherapy and immunotherapy are standard treatments for advanced prostate cancer, yet their efficacy is often limited by drug resistance and an immunosuppressive, "cold" tumor microenvironment (TME). To address these challenges, we develop a reactive oxygen species (ROS)-responsive nanoparticle, PTX-Zn NP, for the co-delivery of paclitaxel (PTX) and zinc ions (Zn2+). Within tumor cells, elevated ROS triggers the release of PTX, promoting micronuclei formation and cytosolic double-stranded DNA exposure. Concurrently, Zn2+ amplifies cGAS-STING signaling by enhancing cGAS-DNA binding and inducing mitochondrial damage. In vitro, PTX-Zn NP suppressed tumor cell proliferation, generated ROS and micronuclei, and activated the STING pathway to promote dendritic cell maturation. In vivo, PTX-Zn NP preferentially accumulated in prostate tumors, inhibited tumor growth, and reprogrammed the "cold" TME toward a "hot" phenotype. When combined with anti-PD-L1 therapy, PTX-Zn NP significantly improved antitumor efficacy and promoted long-term immune memory. Overall, this dual-action approach provides a promising strategy to overcome both chemoresistance and immune evasion in advanced prostate cancer.