A Tumor Cell Membrane-Coated CD40 Ligand-Encoding Oncolytic Adenovirus Serves as a Potent Nano-Vaccine for Ovarian Cancer Immunotherapy.

Abstract

Oncolytic virus-based vaccines for advanced ovarian cancer have limitations owing to their receptor-dependent tropism, host immune clearance, and ascites-mediated viral neutralization. To mitigate these drawbacks, a novel nano-vaccine platform was developed by incorporating immunostimulatory oncolytic adenoviruses within tumor cell membranes. This biomimetic system enabled sustained antigen release and tumor-localized delivery of co-stimulatory molecules, creating immunological hotspots through in situ viral replication and PANoptosis. The nano-vaccine achieved selective viral tropism with a 36.3:1 tumor-to-liver biodistribution ratio (vs. 1.0:1 for the uncoated virus) while resisting immune/ascites interference. Oncolysis triggered immunogenic cell death, which released damage-associated molecular patterns and drove systemic antitumor immunity. Notably, the platform enriched stem-like TCF1⁺PD-1⁺CD8⁺ T cell reservoirs that demonstrate enhanced effector differentiation upon PD-1 checkpoint blockade. In models of peritoneal carcinomatosis, combination therapy with αPD-1 induced complete tumor eradication in 50% of mice and significantly prolonged survival. Furthermore, a synergistic efficacy was observed when the nano-vaccine was administered with cisplatin, a frontline chemotherapeutic agent. This virotherapy paradigm synergizes vaccination and immune reprogramming to dismantle immunosuppressive networks, thereby offering transformative potential against ovarian cancer.