Ovarian Cancer (OC) remains a major cause of gynecologic cancer-related mortality, and the clinically introduction of poly (ADP-ribose) polymerase inhibitors (PARPi) has substantially improved the progression-free survival. However, the long-term efficacy of PARPi is severely compromised by the restoration of homologous recombination repair and enhanced drug efflux. Here, we report a reactive oxygen species (ROS)-responsive nanoplatform (DP@NP) for the codelivery of the PARPi Niraparib and the DOT1L inhibitor (DOT1Li) SGC0946 to overcome these limitations. DP@NP can be triggered by ROS in cancer cells, and the released PARPi exerts anticancer activity by inducing DNA damage. Concurrently, the released DOT1Li further promotes the accumulation of DNA damage by inhibiting PARPi efflux and impairing DNA repair, thereby amplifying the anticancer effects of PARPi. Mechanistically, the resulting accumulation of cytosolic double-stranded DNA (dsDNA) robustly activates the STING signaling pathway, leading to reprogramming of the tumor immune microenvironment (TIME) from an immunologically “cold” to a “hot” state. In vivo, DP@NP exhibits efficient tumor targeting and prolonged intratumoral retention, resulting in pronounced antitumor efficacy across multiple OC models. Notably, DP@NP-mediated immune remodeling and upregulation of PD-L1 expression significantly enhance tumor responsiveness to immune checkpoint inhibitors (ICIs), as evidenced by the superior therapeutic outcomes observed in an OC peritoneal metastasis model treated with combined DP@NP and ICI therapy. Collectively, this study establishes DP@NP as a mechanistically integrated nanotherapeutic strategy that enhances PARPi efficacy while sensitizing OC to immunotherapy, offering a promising approach to overcome the limited therapeutic durability of PARPi.

Yi Sun will complete her PhD at the age of 39 from Peking Union Medical College, China. She has published 6 SCI-indexed papers to date, with a cumulative impact factor exceeding 30.