Pt(II)-NHC Complex Induces ROS-ERS-Related DAMP Balance to Harness Immunogenic Cell Death in Hepatocellular Carcinoma

Immunogenic cell death (ICD) can engage a specific immune response and establish a long-term immunity in hepatocellular carcinoma (HCC). Herein, we design and synthesize a series of Pt­(II)-N-heterocyclic carbene (Pt­(II)-NHC) complexes derived from 4,5-diarylimidazole, which show strong anticancer activities in vitro. Among them, 2c displays much higher anticancer activities than cisplatin and other Pt­(II)-NHC complexes, especially in HCC cancer cells. In addition, we find that 2c is a type II ICD inducer, which can successfully induce endoplasmic reticulum stress (ERS) accompanied by reactive oxygen species (ROS) generation and finally lead to the release of damage-associated molecular patterns (DAMPs) in HCC cells. Importantly, 2c shows a great anti-HCC potential in a vaccination mouse model and leads to the in vivo immune cell activation in the CCl4-induced liver injury model.免疫原性细胞死亡（Immunogenic cell death, ICD）可触发特异性免疫应答，并在肝细胞癌（hepatocellular carcinoma, HCC）中建立长期免疫。本研究设计并合成了一系列源自4,5-二芳基咪唑的铂(II)-氮杂环卡宾（Pt(II)-N-heterocyclic carbene, Pt(II)-NHC）配合物，该类配合物在体外展现出强劲的抗癌活性。其中，化合物2c的抗癌活性远高于顺铂及其他铂(II)-氮杂环卡宾配合物，在肝癌细胞中尤为显著。此外，本研究发现2c属于II型免疫原性细胞死亡诱导剂，可成功诱导内质网应激（endoplasmic reticulum stress, ERS），伴随活性氧（reactive oxygen species, ROS）生成，最终促使肝癌细胞释放损伤相关分子模式（damage-associated molecular patterns, DAMPs）。值得注意的是，2c在疫苗接种小鼠模型中展现出优异的抗肝癌潜力，并在四氯化碳（CCl4）诱导的肝损伤模型中实现了体内免疫细胞活化。