Sono-responsive self-assembled coppery nanodrugs amplify cuproptosis for high-efficiency cancer chemo-immunotherapy

Cuproptosis-based therapy holds great promise in boosting systemic anti-tumor efficacy, especially when synergistically combined with sonodynamic therapy, which amplifies oxidative stress and offers superior tissue-penetration capabilities. In this study, a cuproptosis amplifier (DTX/TPPS-Cu) was developed through copper ion-mediated coordinative self-assembly of the sonosensitizer porphyrin (TPPS) and the chemotherapeutic agent docetaxel (DTX), aiming to boost cancer chemo-immunotherapy. DTX/TPPS-Cu nanoparticles internalized by tumor cells can be activated by intracellular glutathione (GSH) to release Cu⁺, which induces the oligomerization of lipoylated proteins, thereby triggering proteotoxic stress and irreversible cuproptosis. Upon ultrasound irradiation, the released TPPS generates a sonodynamic effect that further depletes excessive GSH, thereby preventing Cu⁺ chelation and amplifying cuproptosis in tumor cells, ultimately sensitizing DTX-mediated chemotherapy. More importantly, the significantly elevated reactive oxygen species levels and highly efficient cuproptosis contribute to the reversal of the immunosuppressive tumor microenvironment, thereby promoting immunogenic cell death and eliciting robust systemic anti-tumor immune responses for the tumor eradication. Thus, we propose a precisely regulated sonodynamic cuproptosis strategy to amplify chemo-immunotherapeutic efficacy, potentially heralding a new paradigm in cancer therapy.