Repurposing clinical iron oxide agents for mild hyperthermia-assisted cancer therapy

Abstract

Cancer remains a global challenge demanding innovative therapeutic strategies, particularly for metastatic cases. While iron oxide nanoparticles have gained clinical approval as iron supplements or imaging contrast agents, their standalone potential for cancer therapy remains largely unexplored. Here, we report that both photo- and ultrasound-induced mild hyperthermia (∼43°C) can enhance iron oxide toxicity through amplified Fenton reactions and sensitize tumor cells to ferroptosis. To enhance translational potential, we refine this platform with a clinically approved iron agent of ferumoxytol and ultrasound, termed ferrultrasonic therapy (FUT). FUT can induce immunogenic cell death across multiple xenograft models and can trigger robust anticancer immune responses. Notably, FUT can significantly prolong the survival time of mice with peritoneal metastasis and achieved a 37.5% complete cure rate by 8 weeks. Overall, our work presents a translatable anticancer strategy validated in patient-derived xenograft humanized mouse models, bridging the gap in repurposing clinically approved iron agents for oncology applications.