A glucose metabolism-targeted nanoplatform amplifies disulfidptosis-associated immunogenic cell death in triple-negative breast cancer.

Disulfidptosis is a metabolism-dependent form of cell death driven by disulfide stress that induces actin cytoskeletal collapse in SLC7A11-high cells under glucose deprivation. However, strategies to therapeutically exploit this vulnerability remain underdeveloped. Given the high dependence of triple-negative breast cancer (TNBC) on glucose metabolism, we engineered a tumor microenvironment-responsive MnOx nanoplatform for sustained delivery of the GLUT1 inhibitor BAY-876 and concurrent glutathione (GSH) depletion. Within this integrated system, BAY-876 restricts GLUT1-mediated glucose uptake, thereby reducing the availability of reduced nicotinamide adenine dinucleotide phosphate (NADPH), impairing the reduction of cystine to cysteine, and promoting intracellular cystine accumulation. In parallel, MnOx undergoes GSH-triggered degradation in the GSH-rich intracellular environment of tumor cells, releasing Mn2+ and consuming intracellular GSH, thereby weakening cellular antioxidant defenses. Glucose restriction-induced NADPH depletion and MnOx-mediated GSH depletion synergistically intensify disulfide stress. Beyond direct cytotoxicity, the resulting metabolic and redox imbalance promotes the surface exposure and extracellular release of damage-associated molecular patterns (DAMPs), thereby enhancing immunogenic cell death (ICD). This process facilitates dendritic cell maturation and antigen presentation, shifts the immunosuppressive tumor microenvironment toward an immune-active phenotype, and ultimately enhances T-cell-mediated antitumor immunity. Collectively, this work establishes disulfidptosis as a therapeutically actionable metabolic vulnerability and presents a nanotherapeutic strategy that integrates metabolic intervention with immune activation for TNBC treatment.