Proteotoxic stress, caused by the accumulation of abnormal unfolded or misfolded cellular proteins, can efficiently activate inflammatory innate immune response. Initiating the mitochondrial proteotoxic stress might go forward to enable the cytosolic release of intramitochondrial DNA (mtDNA) for the immune-related mtDNA–cGAS–STING activation, which however is easily eliminated by a cell self-protection, i.e., mitophagy. In light of this, a nanoinducer (PCM) is reported to trigger mitophagy-inhibited cuproptotic proteotoxicity. Through a simple metal-phenolic coordination, PCMs reduce the original Cu with the phenolic group of PEG-polyphenol-chlorin e6 (Ce6) into Cu. Cu thereby performs its high binding affinity to dihydrolipoamide S-acetyltransferase (DLAT) and aggregates DLAT for cuproptotic proteotoxic stress and mitochondrial respiratory inhibition. Meanwhile, intracellular oxygen saved from the respiratory failure can be utilized by PCM-conjugated Ce6 to boost the proteotoxic stress. Next, PCM-loaded mitophagy inhibitor (Mdivi-1) protects proteotoxic products from being mitophagy-eliminated, which allows more mtDNA to be released in the cytosol and successfully stimulate the cGAS–STING signaling. and studies reveal that PCMs can upregulate the tumor-infiltrated NK cells by 24% and enhance the cytotoxic killing of effector T cells. This study proposes an anti-tumor immunotherapy through mitochondrial proteotoxicity.

中文翻译：

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Cuprototic 纳米诱导剂驱动的蛋白毒性应激通过激活 mtDNA-cGAS-STING 信号增强癌症免疫治疗

由异常未折叠或错误折叠的细胞蛋白积累引起的蛋白毒性应激可以有效激活炎症先天免疫反应。启动线粒体蛋白毒性应激可能会促进线粒体内 DNA (mtDNA) 的胞质释放，从而实现免疫相关的 mtDNA-cGAS-STING 激活，但这种激活很容易被细胞自我保护（即线粒体自噬）消除。有鉴于此，据报道纳米诱导剂（PCM）可以触发线粒体自噬抑制的铜凋亡蛋白毒性。通过简单的金属-酚配位，PCM将原始Cu与PEG-多酚-二氢卟酚e6 (Ce6)的酚基团还原成Cu。因此，Cu 与二氢硫辛酰胺 S-乙酰转移酶 (DLAT) 具有高结合亲和力，并聚集 DLAT 以实现铜凋亡蛋白毒性应激和线粒体呼吸抑制。同时，PCM 结合的 Ce6 可以利用呼吸衰竭保存的细胞内氧气来增强蛋白毒性应激。接下来，负载 PCM 的线粒体自噬抑制剂 (Mdivi-1) 可保护蛋白毒性产物免于被线粒体自噬消除，从而允许更多的线粒体 DNA 在胞质溶胶中释放，并成功刺激 cGAS-STING 信号传导。研究表明，PCM 可使肿瘤浸润的 NK 细胞上调 24%，并增强效应 T 细胞的细胞毒性杀伤作用。这项研究提出了一种通过线粒体蛋白毒性的抗肿瘤免疫疗法。