Cancer Centre and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR 999078, China; MoE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR 999078, China.
Cancer Centre and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR 999078, China; MoE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR 999078, China.
Biomaterials. 2024 Jun;307:122512. doi: 10.1016/j.biomaterials.2024.122512. Epub 2024 Feb 26.
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. In vitro and in vivo 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.
蛋白毒性应激是由异常未折叠或错误折叠的细胞蛋白积累引起的，可以有效地激活炎症先天免疫反应。启动线粒体蛋白毒性应激可能会导致细胞溶质中内线粒体 DNA（mtDNA）的释放，从而引发免疫相关的 mtDNA-cGAS-STING 激活，但这很容易被细胞自我保护机制即线粒体自噬所消除。有鉴于此，一种纳米诱导剂（PCM）被报道可以触发线粒体自噬抑制的铜毒性蛋白毒性应激。通过简单的金属-酚配位，PCM 将原有的 Cu 与 PEG-多酚-叶绿素 e6（Ce6）的酚基还原为 Cu。Cu 因此表现出与二氢硫辛酰胺 S-乙酰基转移酶（DLAT）的高结合亲和力，并聚集 DLAT 以引发铜毒性蛋白毒性应激和线粒体呼吸抑制。同时，呼吸衰竭中节省的细胞内氧气可被 PCM 缀合的 Ce6 利用，以增强蛋白毒性应激。接下来，PCM 负载的线粒体自噬抑制剂（Mdivi-1）保护蛋白毒性产物不被线粒体自噬消除，从而使更多的 mtDNA 在细胞质中释放，并成功地刺激 cGAS-STING 信号。体内外研究表明，PCM 可以使肿瘤浸润的 NK 细胞上调 24%，并增强效应 T 细胞的细胞毒性杀伤作用。本研究提出了一种通过线粒体蛋白毒性的抗肿瘤免疫疗法。
