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.