Tungstotellurate(VI)‐Based Nanocomposite Inhibits Breast Cancer Proliferation and Metastasis by Enhancing Cuproptosis and Apoptosis

Cuproptosis, characterized by the accumulation of copper (Cu) ions and mitochondrial respiration modulation, holds great potential in cancer therapy. As a newly defined mode of cell death regulation, the mechanisms of copper efflux and high intracellular levels of reducing substances may impair cuproptosis efficacy. To address this, a nanocomposite designated POM/Cu-SS@HA was constructed, comprising sandwich-type polyoxometalate (POM) Na[(CH₃)₂NH₂]₁₃H[Sc₃(H₂O)₂Te₂W₂₄O₉₀]·92H₂O (Sc₃Te₂W₂₄), disulfide-bridged copper-based complexes (Cu-SS), and hyaluronic acid (HA) for targeted delivery. This system induces cuproptosis through copper accumulation, leading to lipoylated protein aggregation and iron-sulfur cluster protein depletion, while concurrently facilitating photothermal therapy (PTT) and apoptosis. The POM (Sc₃Te₂W₂₄) cluster exhibited potent antitumor effects via p53-dependent apoptotic pathway reactivation. In vitro studies demonstrated over 85.6% inhibition rate against 4T1 breast cancer cells when combining POM/Cu-SS@HA with 808 nm NIR irradiation. In vivo results showed 92.8% tumor growth suppression compared to the controls. Transcriptome analysis further identified altered expression profiles in glutathione (GSH) metabolism and mitochondrial function-related genes, confirming the dual induction of cuproptosis and apoptosis. These findings establish a synergistic nanotherapeutic strategy with enhanced efficacy for breast cancer treatment.