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

ABSTRACT

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 Cu ²⁺ 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 Cu ²⁺ 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.