Cuproptosis is a newly recognized copper-dependent nonapoptotic form of cell death, which stimulate studies exploring copper-based nanomaterials to treat cancer through distinct mechanistic action. However, it remains a challenge to completely eradicate tumors via monotherapy. Herein, a copper-doped BiSe_x (CBS) nanozyme was developed to boost αPD-L1-mediated immune checkpoint blocking (ICB) via synergetic apoptosis/cuproptosis-induced immunogenic cell death (ICD). The defect-engineered CBS nanozyme exhibits strong peroxidase-mimicking activities and generates abundant reactive oxygen species (ROS) production causing cell apoptosis, which could be further augmented by NIR photoirradiation. Meanwhile, the CBS could cause mitochondrial lipoylated protein aggregation, leading to cell cuproptosis. The photothermal/catalytic/cuproprosis synergistic therapy triggered by CBS nanozyme combined with αPD-L1 antibody effectively inhibits the growth of primary tumors and distant tumors in prostate cancer model. Furthermore, CBS nanozyme exhibited significant germicidal effect in wound infection. Collectively, this work provides a new insight into cancer treatment of copper-based nanozyme based on cuproptosis/apoptosis-related combined therapy.

铜中毒是一种新认识的铜依赖性非凋亡细胞死亡形式，它刺激了探索铜基纳米材料通过独特的机制作用治疗癌症的研究。然而，通过单一疗法彻底根除肿瘤仍然是一个挑战。在此，开发了一种铜掺杂的 BiSe _x (CBS) 纳米酶，通过协同凋亡/铜中毒诱导的免疫原性细胞死亡 (ICD) 来增强 αPD-L1 介导的免疫检查点阻断 (ICB)。缺陷工程CBS纳米酶表现出很强的过氧化物酶模拟活性，并产生大量活性氧（ROS），导致细胞凋亡，近红外光照射可以进一步增强这种作用。同时，CBS可引起线粒体脂酰化蛋白聚集，导致细胞铜凋亡。CBS纳米酶联合αPD-L1抗体引发的光热/催化/铜协同治疗可有效抑制前列腺癌模型中原发肿瘤和远处肿瘤的生长。此外，CBS纳米酶对伤口感染表现出显着的杀菌作用。总的来说，这项工作为基于铜凋亡/细胞凋亡相关联合疗法的铜基纳米酶的癌症治疗提供了新的见解。