Cuproptosis is an emerging programmed cell death, displaying great potential in
cancer treatment. However, intracellular
copper content to induce cuproptosis is unmet, which mainly ascribes to the intracellular pumping out equilibrium mechanism by
copper exporter ATP7A and ATP7B. Therefore, it is necessary to break such export balance mechanisms for desired cuproptosis. Mediated by
diethyldithiocarbamate (DTC) coordination, herein a strategy to efficiently assemble
copper ions into
polydopamine nanostructure (PDA-DTC/Cu) for reprogramming
copper metabolism of
tumor is developed. The deposited Cu2+ can effectively trigger the aggregation of lipoylated
proteins to induce cuproptosis of
tumor cells. Beyond elevating intracellular
copper accumulation, PDA-DTC/Cu enables to break the balance of
copper metabolism by disrupting mitochondrial function and restricting the
adenosine triphosphate (
ATP) energy supply, thus catalytically inhibiting the expressions of ATP7A and ATP7B of
tumor cells to enhance cuproptosis. Meanwhile, the killed
tumor cells can induce immunogenic cell death (ICD) to stimulate the immune response. Besides, PDA-DTC/Cu NPs can promote the repolarization of tumor-associated macrophages (TAMs ) to relieve the
tumor immunosuppressive microenvironment (TIME). Collectively, PDA-DTC/Cu presented a promising "one stone two birds" strategy to realize
copper accumulation and inhibit
copper export simultaneously to enhance cuproptosis for 4T1 murine
breast cancer immunotherapy.