细胞凋亡和铜凋亡的协同作用，以及免疫系统的激活，为增强三阴性乳腺癌（TNBC）的疗效提供了一种有前景的方法。在这里，合成了两种前药：活性氧（ROS）响应性前药 PEG-TK-DOX 和谷胱甘肽（GSH）响应性前药 PEG-DTPA-SS-CPT。这些前药通过自组装和螯合 Cu2 来制备同时负载阿霉素 (DOX)、喜树碱 (CPT) 和 Cu2 的纳米颗粒 PCD@Cu。 TNBC细胞中ROS和GSH水平升高破坏了PCD@Cu结构，导致Cu、DOX和CPT的释放以及GSH的消耗。 DOX 和 CPT 在 TNBC 细胞中引发细胞凋亡和免疫原性细胞死亡 (ICD)。同时，PCD@Cu 下调铜转运 ATP 酶 2 (ATP7B) 的表达，导致 TNBC 细胞中铜离子显着积累。这进一步诱导了硫辛酸二氢硫辛酰胺 S-乙酰转移酶 (DLAT) 的聚集和铁硫 (Fe-S) 簇蛋白的下调，最终导致 TNBC 中的铜凋亡和 ICD。体外和体内实验证实，PCD@Cu可诱导TNBC细胞凋亡和铜凋亡，并激活免疫系统，表现出强大的抗肿瘤能力。此外，PCD@Cu 表现出优异的生物安全性。总体而言，这项研究为有效的 TNBC 治疗提供了一种有前景的策略。© 2024 Wiley‐VCH GmbH。

The synergistic effect of apoptosis and cuproptosis, along with the activation of the immune system, presents a promising approach to enhance the efficacy against triple-negative breast cancer (TNBC). Here, two prodrugs are synthesized: a reactive oxygen species (ROS)-responsive prodrug PEG-TK-DOX and a glutathione (GSH)-responsive prodrug PEG-DTPA-SS-CPT. These prodrugs are self-assembled and chelated Cu2+ to prepare nanoparticle PCD@Cu that simultaneously loaded doxorubicin (DOX), camptothecin (CPT), and Cu2+. The elevated levels of ROS and GSH in TNBC cells disrupted the PCD@Cu structure, leading to the release of Cu+, DOX, and CPT and the depletion of GSH. DOX and CPT triggered apoptosis with immunogenic cell death (ICD) in TNBC cells. Simultaneously, PCD@Cu downregulated the expression of copper transporting ATPase 2 (ATP7B), causing a significant accumulation of copper ions in TNBC cells. This further induced the aggregation of lipoylated dihydrolipoamide S-acetyltransferase (DLAT) and downregulation of iron-sulfur (Fe-S) cluster proteins, ultimately leading to cuproptosis and ICD in TNBC. In vitro and in vivo experiments confirmed that PCD@Cu induced apoptosis and cuproptosis in TNBC and activated the immune system, demonstrating strong anti-tumor capabilities. Moreover, PCD@Cu exhibited an excellent biosafety profile. Overall, this study provides a promising strategy for effective TNBC therapy.© 2024 Wiley‐VCH GmbH.