Objective To investigate the mechanism by which INKA2-AS1 promotes hepatocellular carcinoma(HCC)migration,invasion,and macrophage-related immunosuppression.Methods Based on the Cancer Genome Atlas Program(TCGA)-HCC data and Genotype-Tissue Expression(GTEx)databases,differentially expressed genes were analyzed in 374 HCC tissues and 160 normal liver tissues.Survival analysis was used to investigate the relationship between INKA2-AS1 and the prognosis of HCC patients.Cox regression analysis was performed on INKA2-AS1.The relationship between INKA2-AS1 and immune infiltration in HCC tissues was analyzed using the Tumor Immune Estimation Resource Database.A total of 90 HCC patients were recruited from the Department of Hepatobiliary Surgery,Chongqing Hygeia Hospital from January 2019 to January 2021.The HCC tissues and adjacent normal tissues were collected.Hepa 1-6 liver cancer cells were grouped into:normal control(NC),INKA2-AS1,siNC and siINKA2-AS1.INKA2-AS1 was overexpressed and silenced by transfection.The proliferation,migration and invasion of cells in each group were detected by CCK-8,EdU,TUNEL,wound healing and Transwell assays.Each group of Hepa 1-6 cells were co-cultured with macrophages to analyze their effects on macrophages.Twenty nude mice(SPF grade,4 weeks old,15～19 g,half male and half female)were randomly divided into 4 groups(n=5):NC,INKA2-AS1,siNC and siINKA2-AS1.Tumor-bearing nude mouse models were established by subcutaneous injection of INKA2-AS1 silenced and overexpressed Hepa1-6 cells.The effect of INKA2-AS1 on tumor volume and mass were detected.Macrophage immunity was analyzed by Western blot analysis of IL-10 and FAP protein levels in tumor tissues.Results The level of INKA2-AS1 in HCC tissues was significantly higher than that in normal tissues(P<0.05).INKA2-AS1 was associated with the histological grade,pathological stage of HCC(P<0.05).The survival rate(P=0.05),disease-specific survival(P=0.036)and progression-free interval(P=0.024)of HCC patients with high INKA2-AS1 expression were significantly lower than those of patients with low INKA2-AS1 expression.The level of INKA2-AS1 in HCC tissues was significantly higher than that in adjacent normal tissues(P<0.05).Cox regression analysis showed that INKA2-AS1 was an independent predictor of OS in HCC patients(P=0.005).INKA2-AS1 expression was associated with immune cells such as T cells and macrophages.The proliferation,migration,and invasion abilities of the siINKA2-AS1 group were lower than those of the siNC group(P<0.05),the apoptotic rate was higher than that of the siNC group(P<0.05),and inhibited the expression of IL-10 and FAP at mRNA and protein levels in co-cultured macrophages(P<0.05).The proliferation,migration and invasion abilities of the INKA2-AS1 group were higher than those of the NC group(P<0.05),the apoptotic rate was lower than that of the NC group(P<0.05),and promoted the expression of IL-10 and FAP at mRNA and protein levels in co-cultured macrophages(P<0.05).The tumor volume and mass of the siINKA2-AS1 group were lower than those of the siNC group(P<0.05),while the tumor volume and mass of the INKA2-AS1 group were higher than those of the NC group(P<0.01).The levels of IL-10 and FAP proteins in tumor tissues of the siINKA2-AS1 group were lower than those of the siNC group(P<0.05),while the levels of IL-10 and FAP proteins were increased(P<0.05).Conclusion INKA2-AS1 increment is related to poor prognosis of HCC patients,and the molecule promotes the proliferation and metastasis of HCC cells and induces the transformation of tumor-associated macrophages.