In summary, our study uncovered and validated a Tregs-related prognostic model that could identify TME- exhausted subpopulations and revealed that PD1/PD-L1 inhibitors could alter the expression levels of HMOX1, MMP9, and TNFRSF11B in Hep3B and Huh7 cells, which might help us better understand Tregs infiltration and develop personalized immunotherapy treatments for HCC patients. This evidence concerns the gene TNFRSF11B and hepatocellular carcinoma.