Ultrasound‐Activated Ce(IV)‐Integrated Biomimetic Nanoplatform for Oxygenation‐Reinforced Gas‐Sonodynamic Ferroptosis and cGAS–STING‐Driven Antitumor Immunity

ABSTRACT

Immunologically “cold” tumors remain poorly responsive to immunotherapy because hypoxia‐limited oxidative therapy, insufficient immunogenic tumor‐cell death, and dysfunctional T‐cell responses restrict the transition from local tumor destruction to systemic antitumor immunity. Here, an ultrasound‐responsive Ce(IV)‐integrated biomimetic nanoplatform, TcEM@Ce‐P4CO@M, is developed to address these barriers. Ce ⁴⁺ /Ce ³⁺ redox cycling promotes H ₂ O ₂ decomposition and O ₂ generation, sustaining ultrasound‐triggered reactive oxygen species production under hypoxic conditions. Concurrently, P4CO‐derived carbon monoxide contributes to mitochondrial oxidative stress and lipid peroxidation. Endogenous iron‐homeostasis remodeling and impairment of the SLC7A11/glutathione (GSH)/glutathione peroxidase 4 (GPX4) antioxidant defense further favor ferroptosis‐associated tumor‐cell injury. Mitochondrial dysfunction and DNA damage are accompanied by enhanced stimulator of interferon genes (STING)‐associated signaling, while co‐delivered MSA‐2 further reinforces STING‐mediated innate immune activation, collectively contributing to an immunogenic environment that supports dendritic‐cell maturation. The engineered tumor‐derived membrane promotes tumor‐associated delivery and provides CD86‐mediated costimulation and anti‐TIM‐3‐mediated checkpoint modulation. In 4T1 tumor models, this coordinated cascade suppresses primary tumors, inhibits non‐irradiated distant tumors, reduces experimental pulmonary metastatic burden, and remodels the tumor immune microenvironment. Collectively, TcEM@Ce‐P4CO@M converts hypoxia‐limited local sonodynamic injury into ferroptosis‐linked innate‐to‐adaptive systemic antitumor immunity.