化学
免疫系统
糖酵解
重编程
免疫疗法
癌症研究
细胞生物学
活性氧
体内
新陈代谢
下调和上调
细胞凋亡
细胞
PD-L1
程序性细胞死亡
肿瘤细胞
纳米技术
肿瘤微环境
生物物理学
代谢途径
生物化学
瓦博格效应
作者
Danyang Li,Enna Ha,Yaoyao Zhu,Zhenli Zhou,Yan Li,Shuqing He,Shaolong Kuang,Lihai Zhang,Junqing Hu
标识
DOI:10.1038/s41467-025-66657-0
摘要
Nanozymes capable of inducing metabolic reprogramming and activating the immune response without external stimuli in vivo are highly pursued for malignant tumor therapy. In this paper, a PtIrFeMoZn high-entropy alloy (HEA) nanozyme is designed and synthesized via a simple one-step hydrothermal method. The HEA nanozymes not only trigger apoptosis and ferroptosis via cascade biocatalysis, thereby enhancing immunogenicity, but also enhance the immune effect by targeting the glycolytic pathway. It is worth mentioning that a simple pre-treatment of nanozymes by alternating current (AC) yielded much better therapeutic and immuno-effect. The ‘AC-treated’ nanozymes exhibit an excellent synergy of peroxidase-like (POD-like), myeloperoxidase-like (MPO-like), and glutathione peroxidase-like (GPx-like) activities, generating a sufficient reactive oxygen species (ROS) storm. Additionally, two immune pathways (ICD and the cGAS-STING) are activated simultaneously. Furthermore, the production of HClO and the depletion of NADH can regulate metabolism, further disrupting the equilibrium of the glycolysis process. This not only increases the cell death but also enhances the immune response in female tumor-bearing mice. This study proposes a multi-pronged therapeutic strategy that can significantly activate anti-tumor immunotherapeutic effects through ROS storm, GSH/NADH oxidation, and lactate/ATP depletion, triggering apoptosis/ferroptosis/immunotherapy. These findings hold significant promise for inspiring the development of HEA nanozymes for tumor immunotherapy. Nanozymes that can activate immune response without external stimuli could benefit malignant tumor therapy. Here, the authors report high-entropy alloy nanozymes that allow a multi-pronged strategy for activating anti-tumor immunotherapeutic effects, and reveal that using alternating current to pre-treat these nanozymes before in vivo administration can enhance the therapeutic and immuno-effect.
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