NIR-II Light-Triggered Electron Flow Initiates Cuproptosis-Centered Thermoelectric-Immunotherapy for Breast Cancer

Cuproptosis, a copper-dependent form of regulated cell death, holds significant promise for oncology, but its therapeutic utility is constrained by the inefficient intratumoral generation of the bioactive Cu⁺ species. To this end, we report a NIR-II light-activatable thermoelectric nanoreactor (Te@PDA-Cu^II) designed to achieve spatiotemporally controlled Cu⁺ production for enhanced cancer therapy. The nanoreactor comprises a tellurium nanorod core, which exhibits a strong thermoelectric effect under 1064 nm light irradiation, coated with a polydopamine (PDA) layer that serves both as a Cu²⁺ chelation scaffold and an electron-conducting interface. Photothermal activation generates a directional electron flow from the Te core, which is efficiently relayed through the PDA layer to reduce surface-bound Cu²⁺ to Cu⁺. Such in situ valence conversion potently triggers cuproptosis via dihydrolipoamide S-acetyltransferase (DLAT) aggregation and Fe─S cluster destabilization. The ensuing cuproptosis initiates immunogenic cell death (ICD), promoting dendritic cell maturation and cytotoxic T lymphocyte infiltration. In orthotopic and metastatic breast cancer models, this thermoelectric-immunological cascade not only eradicates primary tumors but also synergizes with aPD-1 checkpoint blockade to suppress distant metastases and establish durable immune memory. This work establishes a physical energy-driven strategy for precise cuproptosis activation and demonstrates its potential to amplify cancer immunotherapy.