目前，针对晚期肝癌无标准和令人满意的治疗方法。多靶点酪氨酸激酶抑制剂（multi-target tyrosine kinase inhibitor，MTKI）联合NK细胞对肝癌细胞具有协同杀伤作用：一方面，MTKI能阻断肿瘤细胞增殖和血管生成信号通路促进细胞凋亡；另一方面，MTKI诱导肿瘤细胞表达NK细胞活化性配体（natural killer group 2 member D ligand，NKG2DL），促进肿瘤细胞对NK细胞杀伤的敏感性。MTKI诱导肿瘤细胞表达NKG2DL，主要通过DNA损伤修复反应分子和细胞凋亡通路与转录因子NF-κB（nuclear factor-κB)之间相互作用，活化由NF-κB2和RelB组成的旁路途径调节NKG2DL的转录和表达。MTKI通过NF-κB旁路途径诱导肿瘤表达NKG2DL的分子机制为MTKI联合NK细胞治疗肝细胞癌提供了理论依据。

There are no standard effective systemic therapies for patients with hepatocellular carcinoma diagnosed at advanced stage, who have poor prognosis. It has been shown that Multi-target tyrosine kinase inhibitors (MTKIs) and adoptive NK cell immunotherapy have synergistic effect on hepatocellular carcinoma cells. In addition to blocking cell proliferation and angiogenesis signal pathway in tumor tissue to promote apoptosis, MTKIs also induce the expression of natural killer group 2 member D ligands (NKG2DLs) on tumor cells, which interact with NKG2D on NK cells to activate their antitumor activity. It is evident that MTKIs act on signaling molecules involved in DNA damage response, leading to activation of the alternative NF-κB complex that consists of NF-κB2 and RelB, which in turn increases the transcription of NKG2DLs. These results provided a mechanistic rationale for therapy using MTKIs together with adoptive NK cell transfer in the treatment of advanced hepatocellular carcinoma.

国家自然科学青年基金资助项目（No. 81302372，81300431）；南方医科大学珠江医院优秀中青年人才项目资助（No.201206012)