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.

中文翻译：

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二氯乙酸的线粒体靶向聚合物胶束诱导细胞焦亡以增强骨肉瘤免疫治疗

据报道，细胞焦亡可以改善免疫抑制性肿瘤微环境，并且可能是增强骨肉瘤治疗的一种策略。线粒体调节可在多大程度上诱导肿瘤细胞焦亡以增强免疫治疗尚未得到表征。我们合成了一种靶向线粒体的聚合物胶束 (OPDEA-PDCA)，其中聚[2-( N -oxide- N , N-二乙氨基）甲基丙烯酸乙酯] (OPDEA) 用于靶向线粒体，共轭二氯乙酸 (DCA) 用于抑制丙酮酸脱氢酶激酶 1 (PDHK1)。该偶联物通过启动线粒体氧化应激诱导细胞焦亡。我们发现 OPDEA-PDCA 靶向线粒体并通过抑制 PDHK1 诱导线粒体氧化应激，导致骨肉瘤细胞系发生免疫原性细胞焦亡。此外，我们发现 OPDEA-PDCA 可以诱导可溶性程序性细胞死亡配体 1 (PD-L1) 分子的分泌。因此，OPDEA-PDCA 和抗 PD-L1 单克隆抗体联合治疗可显着抑制骨肉瘤的增殖并延长 T 细胞活化。这项研究提供了一种通过靶向调节线粒体来启动细胞焦亡的策略，