Simultaneous Activation of Immunogenic Cell Death and cGAS-STING Pathway by Liver- and Mitochondria-Targeted Gold(I) Complexes for Chemoimmunotherapy of Hepatocellular Carcinoma

• Published in: Journal of medicinal chemistry Vol. 67; no. 3; pp. 1982 - 2003
• Main Authors: Li, Fuwei, Wen, Zhenfan, Wu, Chuanxing, Yang, Zhibin, Wang, Zhaoran, Diao, Wenjing, Chen, Dahong, Xu, Zhongren, Lu, Yunlong, Liu, Wukun
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 08-02-2024
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c01785

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 (9a–9l) were designed and synthesized. The superior complex 9b 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, 9b 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.