Interplay between exosomes and the PD-1/PD-L1 axis in hepatocellular carcinoma: Implications for immune escape and immunotherapy.

Hepatocellular carcinoma (HCC) persists as a highly lethal malignancy largely due to its profoundly immunosuppressive tumor microenvironment, which enables tumor cells to evade immune surveillance and limits the effectiveness of immune checkpoint inhibitors (ICIs). Among the mechanisms shaping this immune-refractory landscape, exosomes have emerged as pivotal regulators that both orchestrate and amplify dysfunction of antitumor immunity. These nanoscale vesicles, released by tumor cells, stromal elements, and immune subsets, transport biologically active cargo, including programmed death-ligand 1 (PD-L1), immunomodulatory RNAs, metabolic enzymes, and extracellular matrix components, that directly reinforce the programmed cell death-1 (PD-1)/PD-L1 axis. Exosomal PD-L1 not only mirrors tumor burden but also circulates systemically, maintaining T-cell exhaustion at distant sites and competing with therapeutic antibodies, thereby contributing to both primary and acquired resistance to ICIs. In HCC, diverse exosomal cargoes, including PD-L1-enriched vesicles, macrophage-polarizing microRNAs, CAFs-derived transcriptional activators, and ER stress-induced non-coding RNAs, synergistically elevate PD-L1 expression in tumor and myeloid cells while promoting CD8⁺ T-cell dysfunction, regulatory T-cell expansion, and immune exclusion. Conversely, selected immune-cell-derived or engineered exosomes can counteract this signaling, offering novel strategies to restore antitumor immunity. Circulating exosomal biomarkers such as PD-L1, CCT3, and specific long non-coding RNA (lncRNA) signatures further demonstrate strong predictive value for ICI response. This review synthesizes current mechanistic insights into how exosomes modulate the PD-1/PD-L1 axis in HCC, highlights their utility as liquid biopsy biomarkers, and discusses emerging therapeutic strategies that target exosome-mediated immunosuppression. Understanding this interplay provides a foundation for developing more precise and effective immunotherapeutic approaches for HCC.