TP73-AS1 negatively regulates miR-539, and its knockdown inhibits MMP-8 expression and M2 macrophage polarization. miR-539 overexpression also suppresses M2 polarization by downregulating MMP-8. MMP-8 knockdown limits M2 polarization by inhibiting TGF-β1 signaling. TP73-AS1 knockdown or miR-539 overexpression inhibits HCC tumor growth and M2 macrophage infiltration. Here, MMP8 is linked to hepatocellular carcinoma.