Simultaneous Activation of Immunogenic Cell Death and cGAS-STING Pathway by Liver- and Mitochondria-Targeted Gold(I) Complexes for Chemoimmunotherapy of Hepatocellular Carcinoma.
Fuwei LiZhenfan WenChuanxing WuZhibin YangZhaoran WangWenjing DiaoDahong ChenZhongren XuYunlong LuWukun LiuPublished in: Journal of medicinal chemistry (2024)
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.
Keyphrases
- cell death
- reactive oxygen species
- small molecule
- immune response
- cell cycle arrest
- dendritic cells
- dna damage
- cancer therapy
- single molecule
- cell free
- copy number
- oxidative stress
- gene expression
- endothelial cells
- cystic fibrosis
- endoplasmic reticulum
- transcription factor
- candida albicans
- protein protein
- innate immune