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.