Wireless Electro‐Fenton Overcomes Tumor Electric Field Treatment Resistance

Abstract

ABSTRACT Residual glioblastoma cells surviving Tumor Electric Field Treatment (TEFT) frequently acquire therapeutic resistance, driving fatal recurrence. Integrating sequencing of patient‐derived organoids with resistant models, we identified a metabolic rewiring characterized by GPX4 upregulation and concomitant ACSL4 suppression as the driver of a ferroptosis‐evading phenotype. Uniquely, we harness the resistance‐driving electric field itself as a wireless energy source to fuel a material‐based chemical attack against this antioxidant defense. To breach this barrier, we developed Ba 2 FeNbO 6 (BFNO), a defect‐rich double‐perovskite acting as a wireless electro‐Fenton catalyst. Under TEFT, BFNO harvests electric energy to accelerate Fe‐ion redox cycling, precipitating a catastrophic ROS storm that overwhelms antioxidant defenses and triggers hybrid lysosomal ferroptosis and GSDME‐mediated pyroptosis. This process culminates in immunogenic cell death, resensitizing refractory tumors. Furthermore, combining BFNO with PD‐1 blockade effectively reverses adaptive immune resistance and T‐cell exhaustion, reshaping the immunosuppressive microenvironment. Our study establishes a strategy to repurpose the electric field into a lethal biochemical trigger, overcoming resistance and potentiating immunotherapy in glioblastoma.