自然杀伤 (NK) 细胞是先天免疫的关键成员之一，主要存在于肝脏中，增强针对病毒感染或恶性肿瘤的免疫反应。据报道，NK细胞的细胞数量和功能的变化与慢性肝病（CLD）的发生和进展有关，包括非酒精性脂肪肝病、酒精性肝病和慢性病毒性肝炎。此外，众所周知，NK细胞和肝星状细胞之间的串扰在肝纤维化和肝硬化中发挥着重要作用。特别是，在 CLD 中观察到的 NK 细胞功能受损会导致肝细胞癌 (HCC) 的发生和进展。乙型或丙型肝炎病毒的慢性感染通过产生脱落酶来抵消宿主的抗肿瘤免疫力。可溶性主要组织相容性复合物 I 类多肽相关序列 A (sMICA) 通过脱落酶从细胞表面释放，破坏相互作用并影响 NK 细胞的功能。最近，MICA/B-NK 刺激受体 NK 2 组成员 D (NKG2D) 轴在 HCC 中得到了广泛研究。膜结合 MICA 浓度低或 sMICA 浓度高的 HCC 患者预后不良。因此，逆转 sMICA 介导的 NKG2D 下调已被提议作为增强针对 HCC 的先天和适应性免疫反应的有吸引力的策略。本综述旨在总结近期关于 NK 细胞免疫特征及其在 CLD 和肝细胞癌发生中的作用的研究，并讨论基于 MICA/B-NKG2D 或基于 NK 细胞的 HCC 免疫治疗方法。© 2024 Journal of Gastroenterology and Hepatology Foundation和约翰·威利

Natural killer (NK) cells are one of the key members of innate immunity that predominantly reside in the liver, potentiating immune responses against viral infections or malignant tumors. It has been reported that changes in cell numbers and function of NK cells are associated with the development and progression of chronic liver diseases (CLDs) including non-alcoholic fatty liver disease, alcoholic liver disease, and chronic viral hepatitis. Also, it is known that the crosstalk between NK cells and hepatic stellate cells plays an important role in liver fibrosis and cirrhosis. In particular, the impaired functions of NK cells observed in CLDs consequently contribute to occurrence and progression of hepatocellular carcinoma (HCC). Chronic infections by hepatitis B or C viruses counteract the anti-tumor immunity of the host by producing the sheddases. Soluble major histocompatibility complex class I polypeptide-related sequence A (sMICA), released from the cell surfaces by sheddases, disrupts the interaction and affects the function of NK cells. Recently, the MICA/B-NK stimulatory receptor NK group 2 member D (NKG2D) axis has been extensively studied in HCC. HCC patients with low membrane-bound MICA or high sMICA concentration have been associated with poor prognosis. Therefore, reversing the sMICA-mediated downregulation of NKG2D has been proposed as an attractive strategy to enhance both innate and adaptive immune responses against HCC. This review aims to summarize recent studies on NK cell immune signatures and its roles in CLD and hepatocellular carcinogenesis and discusses the therapeutic approaches of MICA/B-NKG2D-based or NK cell-based immunotherapy for HCC.© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.