Exosomal PD-L1 in hepatocellular carcinoma: Immune evasion mechanisms, diagnostic value, and strategies for therapeutic targeting

Hepatocellular carcinoma (HCC) employs multiple layers of immune evasion, among which exosomal programmed death-ligand 1 (exoPD-L1) has emerged as a key mediator and clinically relevant biomarker. Through vesicular packaging and systemic dissemination, exoPD-L1 reinforces an immunosuppressive milieu beyond the spatial constraints of membrane-bound PD-L1, thereby attenuating cytotoxic lymphocyte activity and facilitating tumor progression. Increasing evidence indicates that circulating exoPD-L1 constitutes a minimally invasive, dynamic biomarker that captures real-time immunological states, with potential utility in predicting responsiveness to immune checkpoint inhibitors, monitoring therapeutic trajectories, and refining patient stratification. Moreover, the biogenesis and functional deployment of exoPD-L1 reveal actionable vulnerabilities-ranging from neutralization and inhibition of vesicular loading to disruption of secretion pathways-that may augment current immunotherapeutic strategies in HCC. Nonetheless, methodological inconsistencies, heterogeneous assay platforms, and limited prospective validation currently constrain clinical translation. This review synthesizes mechanistic insights, evaluates liquid biopsy applications, and outlines emerging therapeutic interventions targeting the exoPD-L1 axis, highlighting priorities for future investigation.