Considering that macrophages are the predominant immune cell subtype expressing both PD-L1 and PD-L2, we propose a new mechanism of how macrophages regulate PD-Ls, during the progression of HCC, macrophages in immune stroma up-regulate PD-Ls in response to IFNγ released by TILs as an adaptive immune-resistance mechanism to suppress CD8+ effector T cell function, thus leading to CD8+ T cell exhaustion/inhibition and poorer survival outcomes (Figure 8). This evidence concerns the gene IFNG and hepatocellular carcinoma.