A stimuli-responsive cuproptosis switch boosts persistent immunotherapy for tumor eradication

Cuproptosis has been identified as a unique copper-dependent cell death mechanism that may provide new opportunities for improving tumor therapy outcomes. For currently developed cuproptosis inducers, nonspecific copper release and low levels of copper accumulation in tumors restrict their clinical applications. To precisely manage copper ion release in vivo, a stimuli-responsive 'cuproptosis switch' was designed as an intelligent platform with pH-sensitive 'off' and 'on' states, thereby inducing cancer-specific cuproptosis while guaranteeing biosecurity. A bilayer copper nanocapsule containing Cu₂O and Cu_2-xSe shells was demonstrated with a switch-like pH-dependent Cu⁺ release profile across a transition pH (6.8) based on their distinct degradable properties. To boost cuproptosis-targeted therapy efficacy, the STING activating agonist MSA-2 was encapsulated in the Cu₂O/Cu_2-xSe nanocapsule for establishing lasting and effective immune responses. Cuproptosis-sensitization effects induced by US irradiation and MSA-2 release were elucidated, including 1) up-regulating Cu influx transporter (SLC31A1) expression and down-regulating Cu efflux transporter (ATP7A) expression to increase intracellular copper overload; 2) facilitating rapid GSH depletion for cuproptosis sensitization in the cytoplasm; 3) increasing mitochondrion membrane permeability for intracellular released Cu⁺ ions entering the mitochondrion. The TME-specific Cu⁺ and MSA-2 release combined with US-irradiated, spatiotemporally located ROS amplification induced tumor-specific cuproptosis, initiated immunogenic cell death, and activated cGAS-STING pathway for boosting robust and durable antitumor efficacy. As a result, complete elimination of primary and distant tumors in mice was achieved at low doses without side effects. The US-sensitized cuproptosis switch may provide opportunities for elimination of local residual tumors and abscopal metastatic foci for final tumor eradication.