Targeting glucose-dependent redox homeostasis overcomes ferroptosis resistance in breast cancer spinal metastasis

Breast cancer spinal metastasis (BC-SM) develops profound therapeutic resistance by adapting to the bone marrow niche. We demonstrate that BC-SM exhibits a more ferroptosis-resistant phenotype than primary tumors, driven by glucose-dependent redox homeostasis that sustains the SLC7A11/GPX4 antioxidant axis. To overcome this, we engineered a biomimetic nanoplatform for the targeted co-delivery of the GLUT1 inhibitor BAY-876 and iron. This system exploits BC-SM’s metabolic vulnerabilities by disrupting glucose-dependent redox, triggering NADPH depletion-driven disulfidptosis while simultaneously facilitating catastrophic ferroptosis. This coordinated intervention dismantles the ferroptosis-resistant program, leading to potent antitumor efficacy in vitro and in vivo. In murine models, the treatment suppressed tumor progression, preserved spinal architecture, and prolonged paralysis-free survival. These outcomes were associated with induced immunogenic cell death and enhanced intratumoral T-cell infiltration, yielding durable systemic immune protection. Collectively, our findings identify glucose-dependent redox as a driver of ferroptosis resistance in BC-SM and offer a mechanistically guided therapeutic paradigm.