Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China.
Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai 210011, P. R. China.
J Med Chem. 2024 Feb 8;67(3):1982-2003. doi: 10.1021/acs.jmedchem.3c01785. Epub 2024 Jan 23.
Induction of immunogenic cell death (ICD) and activation of the cyclic GMP-AMP synthase stimulator of interferon gene (cGAS-STING) pathway are two potent anticancer immunotherapeutic strategies in hepatocellular carcinoma (HCC). Herein, 12 liver- and mitochondria-targeting gold(I) complexes () were designed and synthesized. The superior complex produced a considerable amount of reactive oxygen species (ROS) and facilitated DNA excretion, the ROS-induced ICD and DNA activated the cGAS-STING pathway, both of which evoked an intense anticancer immune response in vitro and in vivo. Importantly, strongly inhibited tumor growth in a patient-derived xenograft model of HCC. Overall, we present the first case of simultaneous ICD induction and cGAS-STING pathway activation within the same gold-based small molecule, which may provide an innovative strategy for designing chemoimmunotherapies for HCC.
诱导免疫原性细胞死亡 (ICD) 和激活环鸟苷酸-腺苷酸合酶刺激干扰素基因 (cGAS-STING) 途径是肝细胞癌 (HCC) 的两种有效的癌症免疫治疗策略。在此，设计并合成了 12 种肝脏和线粒体靶向金 (I) 配合物 ()。优异的配合物 产生了大量的活性氧 (ROS)，并促进了 DNA 排泄，ROS 诱导的 ICD 和 DNA 激活了 cGAS-STING 途径，这两者都在体外和体内引发了强烈的抗癌免疫反应。重要的是， 强烈抑制了 HCC 患者来源异种移植模型中的肿瘤生长。总的来说，我们首次在同一个基于金的小分子中同时诱导 ICD 和激活 cGAS-STING 途径，这可能为设计 HCC 的化学免疫疗法提供了一种创新策略。
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