Bionic nanomedicines for microwave-triggered cuproptosis to enhance cancer immunotherapy

Abstract

Cuproptosis relies on intracellular copper accumulation and shows great potential in tumor therapy. However, the high content of glutathione (GSH) in tumor cells limits its effectiveness. Furthermore, the mechanism of immune activation mediated by cuproptosis remains unclear. To address this, we developed a cancer cell membrane-coated Cu₂O nanoparticle (TC) to induce cuproptosis in tumor cells. After entering tumor cells via homologous targeting, the TC released Cu²⁺ in the acidic microenvironment. Cu²⁺ are subsequently reduced to Cu⁺ generating hydroxyl radicals through the Fenton reaction. These results led to the downregulation of GSH and eventually sensitized cuproptosis. Microwave (MW)-induced hyperthermia further amplifies these effects. Experimental results demonstrate that TC + MW effectively induces 4T1 cancer cells’ cuproptosis both in vitro and in vivo, significantly inhibiting 4T1 tumor growth with minimal systemic toxicity. The treatment also triggered tumor immunogenic cell death and sensitized T-cell-mediated anti-tumor immunity. TC offers a promising strategy for effective cancer cuproptosis and immunotherapy.