上睑下垂
线粒体
癌症研究
免疫疗法
化学
肿瘤微环境
程序性细胞死亡
细胞生物学
细胞凋亡
生物化学
生物
免疫系统
免疫学
肿瘤细胞
作者
Jiakang Jin,Pengcheng Yuan,Wei Yu,Jinti Lin,Ankai Xu,Xiaodan Xu,Jianan Lou,Tao Yu,Chao-Nan Qian,Bing Liu,Jiashi Song,Lijun Li,Ying Piao,Tao Xie,Youqing Shen,Huimin Tao,Jianbin Tang
出处
期刊:ACS Nano
[American Chemical Society]
日期:2022-06-23
卷期号:16 (7): 10327-10340
被引量:76
标识
DOI:10.1021/acsnano.2c00192
摘要
Pyroptosis has been reported to improve the immunosuppressive tumor microenvironment and may be a strategy to enhance osteosarcoma treatment. The extent to which modulation of mitochondria could induce tumor pyroptosis to enhance immunotherapy has not been characterized. We synthesized a mitochondria-targeting polymer micelle (OPDEA-PDCA), in which poly[2-(N-oxide-N,N-diethylamino)ethyl methacrylate] (OPDEA) was used to target mitochondria and the conjugated dichloroacetate (DCA) was used to inhibit pyruvate dehydrogenase kinase 1 (PDHK1). This conjugate induced pyroptosis through initiation of mitochondrial oxidative stress. We found that OPDEA-PDCA targeted mitochondria and induced mitochondrial oxidative stress through the inhibition of PDHK1, resulting in immunogenic pyroptosis in osteosarcoma cell lines. Moreover, we showed that OPDEA-PDCA could induce secretion of soluble programmed cell death-ligand 1 (PD-L1) molecule. Therefore, combined therapy with OPDEA-PDCA and an anti-PD-L1 monoclonal antibody significantly suppressed proliferation of osteosarcoma with prolonged T cell activation. This study provided a strategy to initiate pyroptosis through targeted modulation of mitochondria, which may promote enhanced antitumor efficacy in combination with immunotherapy.
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