Inducing Pyroptosis and Cuproptosis Using Copper Carriers for ROS-Augmented Effective Cancer Therapy

Copper overload shows promise as a therapeutic strategy by disrupting copper homeostasis and inducing cell death pathways. However, challenges include the expulsion of excess copper from cells. This study introduces ZCCP NPs, three-metal MOF nanoparticles that amplify reactive oxygen species (ROS) to enhance cellular copper uptake and reduce copper efflux. In the tumor microenvironment, ZCCP NPs decompose in response to H+ and glutathione (GSH), releasing Zn and Co ions that increase intracellular ROS. Additionally, the TMPyP ligand converts to Phlorin under near-infrared (NIR) excitation, raising tumor site temperature and increasing cancer cell susceptibility to cuproptosis. Elevated ROS and temperature activate the NLRP3 inflammasome and Caspase-1, leading to gasdermin D cleavage and pyroptosis. Enhanced ROS generation impairs mitochondrial function and reduces copper efflux protein ATP7A expression, promoting cuproptosis. This strategy combines pyroptosis and cuproptosis for effective tumor treatment.