环金属化铱（III）配合物通过副死亡途径在HepG2细胞中诱导免疫原性细胞死亡。
Cyclometalated iridium(III) complexes induce immunogenic cell death in HepG2 cells via paraptosis.
发表日期：2023 Sep 06
作者：
Jiaxin Liao, Yuqing Zhang, Minying Huang, Zhijun Liang, Yao Gong, Ben Liu, Yuling Li, Jiaxi Chen, Wei Wu, Zunnan Huang, Jing Sun
来源：
BIOORGANIC CHEMISTRY
摘要：
免疫疗法已被证明能够通过激活先天免疫系统以识别、攻击和清除肿瘤细胞而提供更优越的抗肿瘤效力，而不会严重伤害正常细胞。在本研究中，我们设计并合成了三种新的环金属化的铱(III)配合物（Ir1, Ir2, Ir3），然后评估了它们的抗肿瘤活性。当与HepG2细胞共孵育时，配合物Ir1定位于溶酶体，诱导了副原病（paraptosis）和内质网应激（ER stress）。值得注意的是，Ir1还诱导了免疫原性细胞死亡（ICD），促进了树突状细胞成熟，增强了效应T细胞趋化至肿瘤组织，降低了肿瘤组织中免疫抑制性调节性T细胞的比例，并在全身触发了抗肿瘤免疫的激活。到目前为止，Ir1是首个成功诱导肿瘤细胞ICD的铱（III）配合物基副原病诱导剂的报道。此外，Ir1在不影响细胞周期或活性氧水平的情况下，诱导了HepG2细胞的ICD。© 2023 Elsevier Inc. 保留所有权利。
Immunotherapy has been shown to provide superior antitumor efficacy by activating the innate immune system to recognize, attack and eliminate tumor cells without seriously harming normal cells. Herein, we designed and synthesized three new cyclometalated iridium(III) complexes (Ir1, Ir2, Ir3) then evaluated their antitumor activity. When co-incubated with HepG2 cells, the complex Ir1 localized in the lysosome, where it induced paraptosis and endoplasmic reticulum stress (ER stress). Notably, Ir1 also induced immunogenic cell death (ICD), promoted dendritic cell maturation that enhanced effector T cell chemotaxis to tumor tissues, down-regulated proportions of immunosuppressive regulatory T cells within tumor tissues and triggered activation of antitumor immunity throughout the body. To date, Ir1 is the first reported iridium(III) complex-based paraptosis inducer to successfully induce tumor cell ICD. Furthermore, Ir1 induced ICD of HepG2 cells without affecting cell cycle or reactive oxygen species levels.Copyright © 2023 Elsevier Inc. All rights reserved.