Soluble mediators such as cytokines (IL-6, TNF-α), chemokines (CXCL12, CCL2), and immune checkpoints (PD-L1/PD-1, CTLA-4) further exacerbate the immunosuppressive state of HCC TME, forming a vicious cycle that facilitates tumor immune escape and progression (Gong et al., 2018). This evidence concerns the gene CTLA4 and hepatocellular carcinoma.