癌症免疫学的最新突破将免疫疗法推向了癌症研究的前沿，作为一种有前途的治疗方法，利用人体的免疫系统有效识别和消除癌细胞。在这项研究中，设计、合成了三种新型环金属化 Ir(III) 配合物 Ir1、Ir2 和 Ir3，并在体外评估了其针对多种肿瘤来源细胞系的细胞毒活性。其中，Ir1 表现出最高的细胞毒活性，IC50 值为 0.4 ± 0.1 μM，显示出其显着的抗癌潜力。详细的机制分析表明，Ir1 与 143B 细胞共孵育导致 Ir1 在线粒体和内质网 (ER) 内积累。此外，Ir1 诱导 G0/G1 期细胞周期停滞，同时还降低线粒体膜电位、破坏线粒体功能并引发 ER 应激。有趣的是，在小鼠中，Ir1 诱导的 ER 应激反应破坏了钙稳态，从而引发免疫原性细胞死亡 (ICD)，随后激活宿主抗肿瘤免疫反应，同时抑制体内肿瘤诱导的炎症反应。版权所有 © 2024 Elsevier Inc.版权所有。

Recent breakthroughs in cancer immunology have propelled immunotherapy to the forefront of cancer research as a promising treatment approach that harnesses the body's immune system to effectively identify and eliminate cancer cells. In this study, three novel cyclometalated Ir(III) complexes, Ir1, Ir2, and Ir3, were designed, synthesized, and assessed in vitro for cytotoxic activity against several tumor-derived cell lines. Among these, Ir1 exhibited the highest cytotoxic activity, with an IC50 value of 0.4 ± 0.1 μM showcasing its significant anticancer potential. Detailed mechanistic analysis revealed that co-incubation of Ir1 with 143B cells led to Ir1 accumulation within mitochondria and the endoplasmic reticulum (ER). Furthermore, Ir1 induced G0/G1 phase cell cycle arrest, while also diminishing mitochondrial membrane potential, disrupting mitochondrial function, and triggering ER stress. Intriguingly, in mice the Ir1-induced ER stress response disrupted calcium homeostasis to thereby trigger immunogenic cell death (ICD), which subsequently activated the host antitumor immune response while concurrently dampening the in vivo tumor-induced inflammatory response.Copyright © 2024 Elsevier Inc. All rights reserved.