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

作者：Huize Xia, B Q Li, Ziwen Pan, Yanhua Qi, Qinran Zhang, Q. A. Wang, Weiyang Ma, Bowen Feng, 王代燕, Mingshuo Zhang, Gang Li, Lile Dong, Hao Xue · 发表于：ACS Nano · 年份：2026 · DOI：10.1021/acsnano.6c02969 · 研究领域：Ferroptosis and cancer prognosis、Nanoplatforms for cancer theranostics、Endoplasmic Reticulum Stress and Disease

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 CuBi 2 O 4 (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 Cu 2+ /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 an...