A self-accelerating ‘copper bomb’ strategy activated innate and adaptive immune response against triple-negative breast cancer

Triple-negative breast cancer (TNBC) presents therapeutic challenges due to its aggressive, drug-resistance, and low immunological reactivity. Cuproptosis, an emerging therapeutic modality, is a promising strategic intervention for treating TNBC. Nonetheless, the effectiveness of cuproptosis is compromised by tumor adaptations, including the Warburg effect, increased intracellular glutathione (GSH), and copper efflux, thus breaking the barrier of cuproptosis is the basis for developing cuproptosis-based clinical therapies. Herein, a self-accelerating strategy utilizing a pH-responsive copper framework encapsulating glucose oxidase (GOx), modified with polyethylene glycol (PEG) and tumor-penetrating peptide (tLyp1) has been developed. Upon reaching the acidic tumor microenvironment, the released GOx increases intracellular acidity and hydrogen peroxide (H 2 O 2 ). The elevated intracellular GSH and H 2 O 2 serve as “fuel” to amplify the copper-based catalytic within tumor cells. Concurrently, the reduction of copper efflux proteins (ATP7B) and the depletion of GSH lead to copper overload in tumor cells, leading to cuproptosis via copper overload, mitochondrial disruption, and Fe-S protein instability. This constellation of interrelated events constitutes a potent “Copper Bomb,” which concurrently triggers the immune system and effectively kills the tumor. It robustly engages innate and adaptive immunity via the release of mitochondrial DNA, facilitating the cGAS-STING pathway and precipitating immunogenic cell death. This process reverses the immunosuppressive tumor microenvironment, eliminates tumor cells, and suppresses metastasis, thus offering a novel therapeutic modality for the comprehensive treatment of triple-negative breast cancer (TNBC). • Triple-negative breast cancer therapeutic is limited by its antioxidant defenses and low immune responsiveness. • A self-accelerating strategy can activated by TME and drive mitochondrial respiration to sensitize cuproptosis. • Enhanced ‘copper bomb’ can induced immunity-remodeled by both immunogenic cell death and the mtDNA-cGAS-STING pathway.