Delving into the molecular mechanisms, researchers showed that under hypoxic conditions, SPP1 expression on macrophages was increased and SPP1-positive macrophages affect CAFs leading to ECM remodeling through changes in the expression of collagen, matrix metalloproteinases, or chemokine genes, with a subsequent TIB forming that restrains immune cell infiltration into an HCC tumoral core. Here, SPP1 is linked to hepatocellular carcinoma.