Wireless Electro-Fenton Overcomes Tumor Electric Field Treatment Resistance.

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 Ba₂FeNbO₆ (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.