Bacteria-Based Ammunition for Cascade-Amplified Chemoimmunotherapy of Ovarian Cancer.

Abstract

Ovarian cancer is the deadliest gynecological malignancy due to poor drug targeting, severe toxicity, and an immunosuppressive tumor microenvironment (TME). To address this, a pH/GSH dual-responsive bacterial-nanoparticle system (VNP@BD-Poly) based on attenuated Salmonella VNP20009 (VNP) was developed. A bovine serum albumin (BSA)-doxorubicin (DOX) (BD) complex was functionalized via atom transfer radical polymerization (ATRP) to form BD-Poly, conjugated onto VNP. The system integrates hypoxia tropism, TME-responsive drug release, dual targeting, and antigen capture. In ovarian cancer, it accumulates in hypoxic tumors, releases DOX to induce immunogenic cell death, and activates immunity via a "bacterial sensitization-DOX antigen release-immune cascade" loop. This enhances antitumor immunity, reverses immunosuppression, and suppresses tumor progression with minimal toxicity. This study provides a promising chemoimmunotherapy strategy for ovarian cancer and a versatile platform for solid tumor translational research.