Engineering Oncolytic Virus‐Armed Macrophages for Enhanced Cancer Immunotherapy

ABSTRACT Macrophage‐based immunotherapy holds great promise for solid tumors but is limited by impaired phagocytosis and unstable M1‐type polarization due to immunosuppressive tumor microenvironments. Here, we develop engineered macrophages by conjugating oncolytic adenovirus (OA)‐loaded zeolitic imidazolate framework‐8 (ZIF‐8) onto macrophage surfaces via bioorthogonal chemistry (ZIFOA‐M). This platform leverages localized viral delivery to selectively downregulate “don't eat me” signals (CD47 and CD24) on tumor cells, thereby restoring macrophage phagocytic capacity. Moreover, viral replication within tumors induces immunogenic cell death, releasing major damage‐associated molecular patterns (DAMPs) that sustain M1‐type polarization and promote durable antitumor immunity. ZIFOA‐M also enhances tumor antigen presentation, eliciting robust tumor‐specific T cell responses. Our strategy integrates phagocytosis restoration, microenvironment remodeling, and adaptive immune activation in a single, localized platform. ZIFOA‐M offers a complementary and translatable approach to overcome key barriers in macrophage‐based cancer immunotherapy.