Augmenting cuproptosis and anti-metastatic immunity in breast cancer by copper-based nanoplatform for synergistic immunotherapy via lactate metabolic reprogramming and hypoxia alleviation.

Breast cancer remains a leading cause of cancer-related mortality in women, with the clinical efficacy of immune-checkpoint inhibitors limited by low tumor immunogenicity. Intracellular copper accumulation can induce cuproptosis, an immunogenic form of cell death that enhances antitumor immunity; however, hypoxic, lactate-rich tumor microenvironments stabilize hypoxia-inducible factor-1α (HIF-1α) and activate copper-sequestration programs, suppressing cuproptosis. To address these challenges, a multifunctional liposomal nanoplatform, CuO@Pt-LOx@Lpo nanoparticles (CPLL NPs), is developed. Upon tumor accumulation, the acidic environment triggers the release of lactate oxidase (LOx) and CuO@Pt NPs. LOx converts lactate to pyruvate while generating HO, reducing lactate-HIF-1α signaling and supplying oxidants for copper-driven chemodynamic reactions. CuO catalyzes Fenton-like reactions to produce hydroxyl radicals and release Cu ions, disrupting copper homeostasis and inducing cuproptosis. Platinum nanodots exhibit catalase-like activity, decomposing HO to O, alleviating hypoxia, and further suppressing HIF-1α, enhancing mitochondrial susceptibility to copper-induced lethality. This integrated metabolic and redox modulation promotes immunogenic cell death, activates dendritic cells, increases T-cell infiltration, and inhibits inflammatory cancer-associated fibroblast signaling linked to invasion and metastasis. Overall, CPLL NPs synergistically deplete lactate, relieve hypoxia, restore mitochondrial vulnerability and induce enhanced-cuproptosis, converting immunologically "cold" breast tumors into treatment-responsive lesions.