免疫系统
癌细胞
化学
癌症研究
肿瘤微环境
线粒体
细胞生物学
免疫原性细胞死亡
抗原
癌症免疫疗法
DNA损伤
细胞毒性T细胞
免疫疗法
癌症
生物
免疫学
体外
DNA
生物化学
遗传学
作者
Lingling Lei,Zhe Dong,Li Xu,Fengrui Yang,Baoli Yin,Youjuan Wang,Renye Yue,Guoqiang Guan,Juntao Xu,Guosheng Song,Xiaobing Zhang
出处
期刊:Theranostics
[Ivyspring International Publisher]
日期:2022-01-01
卷期号:12 (14): 6207-6222
被引量:28
摘要
Rationale: Ferroptosis drugs inducing cancer immunogenic cell death (ICD) have shown the potential of immunotherapy in vivo. However, the current ferroptosis drugs usually induce the insufficient immune response because of the low ROS generation efficiency. Methods: Herein, we design zinc-fluorouracil metallodrug networks (Zn-Fu MNs), by coordinating Zn and Fu via facile one-pot preparation, to inactivate mitochondrial electron transport for enhanced ROS production and immune activation. Results: Zn-Fu MNs can be responsive toward acidity and adenosine triphosphate (ATP) with the release of Fu and Zn2+, during which Zn2+ can induce mitochondrion disruption to produce ROS, resulting in ferroptosis of cancer cells and 5-Fu interferes with DNA synthesis in nuclei with 19F-MRI signal to be switched on for correlating drug release. With the synergistic effect of DNA damage and ferroptosis, the cancer cells are forced to promote ICD. Thereby, Zn-Fu MNs exhibit the excellent immune response without any other antigens loading. As a result, the infiltration of T cells within tumor and activation of immune cells in spleen have been greatly enhanced. Conclusions: Combined DNA damage and ferroptosis, Zn-Fu MNs induce the violent emission of tumor associated antigens within cancer cells which will sensitize naive dendritic cells and promote the activation and recruitment of cytotoxic T lymphocytes to exterminate cancer cells. Therefore, the obtained Zn-Fu MNs as ferroptosis inducers can effectively remodel immunosuppressive tumor microenvironment and activate antitumor immune reaction.
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