Mitochondria-Targeting Polymer Micelle of Dichloroacetate Induced Pyroptosis to Enhance Osteosarcoma Immunotherapy

作者：Jiakang Jin, Pengcheng Yuan, Wei Yu, Jinti Lin, Ankai Xu, Xiaodan Xu, Jianan Lou, Tao Yu, Chao Qian, Bing Liu, Jiashi Song, Lijun Li, Ying Piao, Tao Xie, Youqing Shen, Huimin Tao, Jianbin Tang · 发表于：ACS Nano · 年份：2022 · DOI：10.1021/acsnano.2c00192 · 被引用次数：167 · 研究领域：Inflammasome and immune disorders、Immune cells in cancer、Autophagy in Disease and Therapy

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.