The role of PD‑1/PD‑L1 axis in liver diseases

The programmed cell death protein 1 (PD‑1)/programmed death‑ligand 1 (PD‑L1) signaling axis is recognized as a central pathway maintaining immune suppression. Within the liver's inherently tolerogenic microenvironment, parenchymal, non‑parenchymal and immune cell populations are engaged in a dynamic regulatory network mediated by PD‑1/PD‑L1, which serves to preserve immune homeostasis and to balance innate and adaptive immune responses. Aberrant PD‑1/PD‑L1 signaling has been implicated across the disease continuum of many chronic liver disorders, spanning viral hepatitis, fibrosis, and hepatic malignancy. A systematic synthesis is presented of the regulatory roles and recent advances concerning the PD‑1/PD‑L1 axis in viral hepatitis, metabolic dysfunction‑associated fatty liver disease (MAFLD), autoimmune liver diseases and related conditions. Mechanisms regulating PD‑1/PD‑L1 expression and function in hepatocellular carcinoma (HCC) are comprehensively summarized, including tumor microenvironmental determinants, intracellular signaling cascades, post‑translational modifications and epigenetic control. A theoretical framework and novel perspectives are thereby provided for elucidating PD‑1/PD‑L1 dysregulation in chronic liver disease, for identifying candidate biomarkers, and for informing the development of precision immunotherapeutic strategies.