Activated HSC induces mononuclear intrinsic p38 MAPK signaling, which triggers enhancer reprogramming for M-MDSC development and immunosuppression. Treatment with p38 MAPK inhibitors eliminated HSC-M-MDSC crosstalk to prevent HCC growth. Combined with I-BET762 suppressed patient-derived M-MDSC, combined with anti-PD-L1 therapy synergically enhanced TIL, resulting in tumor eradication and prolonged survival in a fibrotic HCC mouse model. This evidence concerns the gene CD274 and hepatocellular carcinoma.