Tumor microenvironment-responsive Cu/CaO2 nanocomposites for amplified pyroptosis and cuproptosis.

Pyroptosis and cuproptosis are promising strategies in cancer therapy. However, strategies to induce cell pyroptosis and cuproptosis are limited by the tumor microenvironment (TME). In this study, a multifunctional copper-based composite nanomaterial (CCS-ICG) was developed to enhance antitumor efficacy through a synergistic combination of chemodynamic therapy (CDT), photodynamic therapy (PDT), and photothermal therapy (PTT), alongside ion interference. This nanomaterial integrates endogenous and exogenous stimulation mechanisms to promote reactive oxygen species (ROS) production. Upon entering tumor cells, CCS-ICG decomposes to release H2O2 and O2, effectively modulating the tumor microenvironment (TME) by elevating H2O2 levels and alleviating hypoxia. Elevated H2O2 enhances the Fenton-like activity of Cu2+, generating toxic OH and boosting CDT, while O2 production improves PDT by promoting 1O2 generation. Additionally, intracellular accumulation of Cu2+ induces cuproptosis, enhancing ROS generation and accumulation, while Ca2+ release triggers calcium overload, amplifying oxidative stress. These mechanisms facilitate significant ROS generation, leading to pyroptosis, immunogenic cell death (ICD), and T cell infiltration, which collectively contribute to a potent antitumor immune response. In vivo and in vitro evaluations reveal that CCS-ICG effectively modulates the TME, exhibits superior antitumor activity, and displays favorable biocompatibility, highlighting its potential as a multimodal platform for synergistic cancer therapy.