Functional heterogeneity of exosomes in hepatocellular carcinoma (Review).

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-associated mortality worldwide. Heterogeneity presents a notable challenge to the diagnosis and treatment of HCC and contributes to poor clinical outcomes. Exosomes serve key roles in intercellular communication among tumor cells and between malignant cells and components of the tumor microenvironment (TME). Accumulating evidence has indicated that exosomal cargo influences hepatocarcinogenesis, tumor progression, metastasis and remodeling of the TME. Accordingly, exosomal components present potential as biomarkers for early HCC detection and as therapeutic targets or delivery vehicles. The present review summarizes exosome biogenesis, isolation, characterization and functional heterogeneity, with particular emphasis on vesicle subpopulations, cellular origin, cargo composition, recipient-cell tropism, disease stage and microenvironmental stress. In addition, the evidence supporting exosome-based biomarkers and therapeutic applications in HCC are critically evaluated. Despite a number of candidates having shown promising results in preclinical or retrospective studies, to the best of our knowledge, no exosome-derived biomarker has yet been incorporated into routine clinical practice for HCC, highlighting the need for methodological standardization and prospective multicenter validation.