免疫原性细胞死亡
癌细胞
线粒体
免疫系统
癌症免疫疗法
巨噬细胞极化
CD8型
巨噬细胞
癌症研究
抗原
细胞毒性T细胞
生物
细胞溶解
转染
细胞生物学
免疫疗法
化学
癌症
免疫学
生物化学
体外
遗传学
基因
作者
Yao Lu,Xiaolong Fan,Qingqing Pan,Bo He,Yuji Pu
摘要
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% vs. 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.
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