以射频消融（radiofrenquency ablation, RFA）为代表的局部微创治疗是继外科切除之后又一种效果确切的治疗方法，但治疗后肿瘤局部复发和肝内新生仍严重影响患者远期生存率。RFA后肝癌局部复发及新生机制急需得到阐明。肿瘤相关巨噬细胞（TAM）对肿瘤转移复发的影响多有报道，而我们在研究中发现RFA在激活抗肿瘤免疫的同时，TAM也被明显激活。TLR4对TAM的激活有重要作用，本项目以TLR4为切入点深入研究RFA后肿瘤局部复发的机制。我们首先建立小鼠原位种植瘤模型及大鼠化学诱导原发癌模型，明确RFA后巨噬细胞的活化对肿瘤局部复发的影响；进一步利用TLR4基因敲除小鼠验证TLR4信号通路对巨噬细胞活化及肿瘤局部复发的影响；最后明确TAM靶向药曲贝替定及TLR4信号通路抑制性药物益生菌和丙酮酸乙脂（EP）对肝癌RFA后巨噬细胞活化的影响及肿瘤局部复发、肝内新生的预防作用

Radiofrequency ablation(RFA) has been proven to provide favorable survival with excellent local control and achieve survival time comparable to surgery in selected patients.Local recurrence is a therapeutic challenge for RFA in treatment of small solid focal malignancies.It is urgent to clatify the mechanism of local recurrence of cancer after therapy with RFA.Many studies have demonstrated that the tumor associated macrophage(TAM) is important factors that promotes tumor recurrence and metastasis.Here,We found that RFA induced heat shock proteins (HSPs) expression and high mobility group box-1 (HMGB1) translocation and the TAM was activated largely in HCC.The studies also show that TLR4 is key for activation of macrophage.In our study ,we focus on the TLR4 signaling pathway to study the profound mechanism of activation of TAM and local recurrence of HCC.Our research based on the modles of liver situ tumor implantation in mouse and DEN induced HCC in rats .Firstly,our purpose is to clear out the impact of RFA on activation of TRL4 and TAM and activation of TRL4 or TAM on HCC local recurrence.Steply,TLR4-Knock out mouse modle was used to charify the impact of TLR4 on activaton of TAM and HCC local recurrence.Finally,trabectedin targeting TAM as well as probiotics and Ethyl pyruvate(EP)against TLR4 were tested and verified the curative effect on local and intrahepatic recurrence of HCC after RFA.