Electric-Field-Driven Ferredoxin 1-Independent Cuproptosis Induction Overcomes Therapy-Induced Resistance in Glioblastoma

Cuproptosis presents a potential therapeutic avenue for Glioblastoma (GBM), yet its efficacy is severely limited by intrinsic and adaptive resistance mechanisms. Here, we identify a critical therapy-induced barrier where standard-of-care interventions, including Temozolomide, radiotherapy, and Tumor Electric-Field Therapy (TEFT), consistently induce a profound downregulation of essential cuproptosis-execution genes such as Ferredoxin 1 (FDX1) and Dihydrolipoamide S-Acetyltransferase (DLAT). This transcriptomic remodeling reveals a universal mechanism of acquired Cuproptosis resistance in recurrent GBM, rendering residual tumor cells refractory to copper toxicity despite their elevated metabolic stress. To overcome this maladaptive remodeling, we engineered an electric-field-responsive CuBi₂O₄ (CBO) nanoplatform to establish an FDX1-independent, upstream-bypass paradigm for copper activation. Crucially, this strategy repurposes TEFT from a purely cytostatic modality into a physical stimulus tool. The external electric field catalyzes a nonenzymatic Cu²⁺/Cu⁺ redox cycle specifically within lysosomes. This process generates a lethal copper pool that bypasses the downregulated FDX1 machinery and translocates to mitochondria, where it converges on lipoylated DLAT-associated Cuproptosis execution. Validated in orthotopic and recurrent GBM models, this approach enforces robust cytotoxicity and activates the cGAS-STING pathway to reverse Immunosuppression. When combined with anti-PD-1 blockade, this TEFT-triggered nanomedicine elicits durable antitumor immunity, offering a versatile strategy to exploit therapy-induced stress states in refractory malignancies.