A Radiation‐Activated and Self‐Cascade Nano‐Immunostimulator Triggers a Potent Abscopal Effect Against Distant Tumors

Abstract Radiotherapy (RT) inhibits local tumors by stimulating reactive oxygen species (ROS) generation, and sometimes suppresses distant tumors known as the abscopal effect. However, the abscopal effect is rarely observed in clinic, due to insufficient tumor‐associate antigens (TAAs) and weak immune stimulation. Here, a radiation‐activated and self‐cascade nano‐immunostimulator (RAIDER) is fabricated to trigger a potent abscopal effect against distant tumors by unleashing cascade‐amplified ROS generation and boosting antigen presentation. After accumulation in tumors, RAIDER undergoes HAase‐triggered deshielding and charge‐reversal, and GE11 enriched liposomal core and CpG are both released. Under following RT, protoporphyrin IX‐induced Cherenkov radiation‐photodynamic therapy (CR‐PDT) elicits ROS generation, leading to disintegration of RAIDER and catalase (CAT) burst release. Meanwhile, by the combination of RT, CR‐PDT, and CAT‐induced O₂ supply, self‐cascade ROS generation is achieved to enhance lysis of tumor cells and release of massive TAAs. Subsequently, the co‐stimulation of TAAs and the released CpG activates dendritic cell maturation to boost antigen presentation, resulting in a strong systemic immune response. Combined with RT, RAIDER exhibits a potent abscopal effect, with an average distant tumor growth inhibition of ≈70.3%. Overall, the strategy amplifies antitumor effect of RT from local to systemic, holding a potential against local and distant tumors.