National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, China.
School of Preclinical Medicine, Chengdu University, Chengdu 610106, China.
J Mater Chem B. 2024 Feb 21;12(8):2006-2014. doi: 10.1039/d3tb02886k.
The way that cancer cells die inspires treatment regimens and cytolytic cuproptosis induced by copper complexes, like copper(II) bis(diethyldithiocarbamate) (CuET), has emerged as a novel therapeutic target. Herein, a triphenylphosphonium-modified CuET (TPP-CuET) is designed to target mitochondrial metabolism, triggering intense immunogenic cuproptosis in breast cancer cells and remodeling tumor-associated macrophages. TPP-CuET enables an enhanced mitochondrial copper accumulation in comparison to CuET (29.0% 19.4%), and severely disrupts the morphology and functions of mitochondria, encompassing the tricarboxylic acid cycle, ATP synthesis, and electron transfer chain. Importantly, it triggers amplified immunogenic death of cancer cells, and the released damage-associated molecular patterns effectively induce M1 polarization and migration of macrophages. Transcriptome analysis further reveals that TPP-CuET promotes antigen processing and presentation in cancer cells through the MHC I pathway, activating the immune response of CD8 T cells and natural killer cells. To the best of our knowledge, TPP-CuET is the first mitochondrial targeted immunogenic cuproptosis inducer and is expected to flourish in antitumor immunotherapy.
癌细胞死亡的方式为治疗方案提供了灵感，而铜配合物诱导的细胞溶解性铜死亡（如二乙基二硫代氨基甲酸铜(II)（CuET））已成为一种新的治疗靶点。在此，设计了一种三苯基膦修饰的 CuET（TPP-CuET）以靶向线粒体代谢，在乳腺癌细胞中引发强烈的免疫原性铜死亡，并重塑肿瘤相关的巨噬细胞。与 CuET（29.0% 19.4%）相比，TPP-CuET 可增强线粒体中的铜积累，并严重破坏线粒体的形态和功能，包括三羧酸循环、ATP 合成和电子传递链。重要的是，它会引发癌细胞增强的免疫原性死亡，释放的损伤相关分子模式可有效诱导 M1 极化和巨噬细胞的迁移。转录组分析进一步表明，TPP-CuET 通过 MHC I 途径促进癌细胞中的抗原加工和呈递，激活 CD8 T 细胞和自然杀伤细胞的免疫反应。据我们所知，TPP-CuET 是首个线粒体靶向免疫原性铜死亡诱导剂，有望在抗肿瘤免疫治疗中大放异彩。
