Nanoscintillator‐Mediated X‐Ray‐Triggered Boosting Transformation of Fe3+ into Fe2+ for Enhancing Tumor Ferroptosis/Immunotherapy

Ferroptosis therapy induced by iron‐catalyzed Fenton reaction has offered enormous opportunities for tumor therapy. Unfortunately, high catalytic activity ferrous (Fe2+)‐based therapeutic agent has remained challenging due to the instability of Fe2+. Herein, an X‐ray‐activated Fe2+ supply platform, termed “PFCN”, containing the core of CaWO4 nanoscintillator to emit ultraviolet (UV) light and Fe3O4 decorated on the surface to deliver excessive Fe2+ is proposed. Under X‐ray excitation, the UV light emitted by CaWO4 can catalyze ferric (Fe3+) to generate Fe2+, which further cascades the Fenton reaction to induce highly toxic hydroxyl radicals generation. More importantly, immunogenic cell death‐associated immunotherapy is simultaneously triggered during this process. Experiments conducted in vitro and in vivo revealed that X‐ray‐triggered PFCN shows superior tumor therapeutic efficacy, contributing i) enhanced radiotherapy; ii) X‐ray‐activated ferroptosis therapy; and iii) ferroptosis/radiotherapy‐induced immunotherapy. Besides, PFCN can be utilized as an MR/CT dual‐mode imaging contrast agent for tumor diagnosis and treatment monitoring. The study provides a novel example of an X‐ray‐activated ferrous‐regeneration platform for imaging‐guided augmenting tumor ferroptosis/immunotherapy An X‐ray‐activated Fe2+ supply system with CaWO4 as the core and surface decorated with Fe3O4 is designed and termed PFCN. CaWO4 can convert X‐ray into UV light to catalyze Fe3+ to Fe2+, which cascades the Fenton reaction, induces ferroptosis，and promotes immunogenic cell death. PFCN+X‐ray shows superior tumor therapeutic efficacy by combining radiotherapy, ferroptosis, and ferroptosis/radiotherapy‐induced immunotherapy.