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

  • J Med Chem. 2024 Feb 8;67(3):1982-2003. doi: 10.1021/acs.jmedchem.3c01785.
Fuwei Li  1 ,  Zhenfan Wen  1 ,  Chuanxing Wu  2 ,  Zhibin Yang  3 ,  Zhaoran Wang  1 ,  Wenjing Diao  4 ,  Dahong Chen  4 ,  Zhongren Xu  1 ,  Yunlong Lu  1  5 ,  Wukun Liu  1  5
Affiliations
  • 1. Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China.
  • 2. Department of General Surgery, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai 210011, P. R. China.
  • 3. Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, Dali University, Dali 671000, P. R. China.
  • 4. Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 210011, P. R. China.
  • 5. State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing 210023, P. R. China.
PMID: 38261008 DOI: 10.1021/acs.jmedchem.3c01785
Abstract

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.

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