Light-Activated CD36-Targeted Cuproptosis Triggers Metabolic-Immune Synergy for Precision Breast Cancer Therapy.

Breast cancer therapy confronts dual challenges of metabolic plasticity-driven drug resistance and immunosuppression. To address this, we developed DCP-TPP, a therapeutic nanoplatform that integrates dysregulation of copper homeostasis and lipid metabolism for precise breast cancer therapy. Leveraging the overexpression of cluster of differentiation 36 (CD36) in breast cancer cells, DCP-TPP employs fatty acid camouflage (PCM) to deliver disulfiram (DSF) and photothermal CuBiS to cancer cells and features triphenylphosphonium (TPP) modification for targeted mitochondrial drug delivery. Near-infrared (NIR) irradiation triggers the phase transition of DCP-TPP's outer layer, inducing spatiotemporal release of DSF to liberate copper ions from inert CuBiS, thereby generating diethyldithiocarbamate-copper complex (CuET). This disrupts copper homeostasis and induces cuproptosis, which subsequently triggers -acetyltransferase (DLAT) aggregation, impairing tricarboxylic acid (TCA) cycle flux, acetyl-CoA production, ATP citrate lyase (Acly)-dependent lipogenesis, and ultimately collapses mitochondrial oxidative phosphorylation. Multiomics profiling revealed oleic acid depletion, arachidonic acid oxidation, and glutathione exhaustion, collectively amplifying metabolic collapse. DCP-TPP-induced cell death enhanced dendritic cell (DC) activation and CD8 T cell infiltration. In breast cancer models, DCP-TPP achieved 90.9% tumor suppression, with 60% of mice resisting rechallenge. By transforming lipid metabolic dependency into a therapeutic vulnerability and coupling it with copper ion toxicity, DCP-TPP offers a promising strategy for breast cancer therapy.