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

作者：Xinzhi Xu, Hang Zhou, Ruixia Hong, Jiaqi Gong, Yujie Wan, Qihuan Fu, Kaifeng Huang, Ying Li, Na Wang, Peng Zhao, Kaiyong Cai, Fang Li · 发表于：Bioactive Materials · 年份：2025 · DOI：10.1016/j.bioactmat.2025.02.019 · 被引用次数：14 · 研究领域：Immune cells in cancer、Nanoplatforms for cancer theranostics、Neuroinflammation and Neurodegeneration Mechanisms

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 ...