Enhanced NK cell activation via eEF2K-mediated potentiation of the cGAS–STING pathway in hepatocellular carcinoma

作者：Yan Xu, Fang Sun, Yuying Tian, Guineng Zeng, Guanglin Lei, Zhifang Bai, Yonggang Wang, Xinlan Ge, Jing Wang, Chaohui Xiao, Zhaohai Wang, Minggen Hu, Jianxun Song, Penghui Yang, Rong Liu · 发表于：International Immunopharmacology · 年份：2024 · DOI：10.1016/j.intimp.2024.111628 · 被引用次数：23 · 研究领域：interferon and immune responses、Immune Cell Function and Interaction、Cancer Immunotherapy and Biomarkers

BACKGROUND: Liver cancer, particularly hepatocellular carcinoma (HCC), is characterized by a high mortality rate, attributed primarily to the establishment of an immunosuppressive microenvironment. Within this context, we aimed to elucidate the pivotal role of eukaryotic elongation factor 2 kinase (eEF2K) in orchestrating the infiltration and activation of natural killer (NK) cells within the HCC tumor microenvironment. By shedding light on the immunomodulatory mechanisms at play, our findings should clarify HCC pathogenesis and help identify potential therapeutic intervention venues. METHODS: We performed a comprehensive bioinformatics analysis to determine the functions of eEF2K in the context of HCC. We initially used paired tumor and adjacent normal tissue samples from patients with HCC to measure eEF2K expression and its correlation with prognosis. Subsequently, we enrolled a cohort of patients with HCC undergoing immunotherapy to examine the ability of eEF2K to predict treatment efficacy. To delve deeper into the mechanistic aspects, we established an eEF2K-knockout cell line using CRISPR/Cas9 gene editing. This step was crucial for verifying activation of the cGAS-STING pathway and the subsequent secretion of cytokines. To further elucidate the role of eEF2K in NK cell function, we applied siRNA-based techniques to effectively suppress eEF2K expression in vitro. For in vivo validation, we developed a tumor-bearing mouse model that enabled us to compare the infiltration...