Immune and Circulating Biomarkers in Hepatocellular Carcinoma: Prognostic and Predictive Relevance for Immunotherapy

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. Immune checkpoint inhibitor (ICI)-based combinations have become the standard first-line systemic therapy, yet objective response rates remain modest (20–36%), and no HCC-specific immune biomarker has been validated to guide selection among standard ICI-based regimens. This review examines the prognostic and exploratory treatment-response associations of potential immune biomarkers in HCC, including markers within the tumor microenvironment (TME) and peripheral blood. A narrative review was conducted evaluating PD-L1 and soluble PD-L1, tumor mutational burden (TMB), tumor-infiltrating lymphocytes (TILs), including machine learning-based assessment, gene expression profiles and tumor-intrinsic pathway alterations, long non-coding RNAs, inflammatory markers (neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, alpha-fetoprotein), gut microbiota, and liquid biopsy analytes (circulating tumor DNA, circulating tumor cells, cell-free DNA). PD-L1 expression shows prognostic associations and inconsistent associations with ICI outcomes; inter-assay heterogeneity further limits its use, and routine PD-L1 testing is not recommended by current guidelines. TMB is generally low in HCC, with inconsistent associations with ICI response. High CD8+ TIL density is associated with improved survival after resection and favorable outcomes in exploratory ICI-treated cohorts, without validated treatment-selective utility. Inflammatory gene signatures and WNT/β-catenin pathway activation are associated with ICI outcomes. Gut microbiome features have shown exploratory associations with anti-PD-1 outcomes, with limited consistency across small datasets. Liquid biopsy markers, particularly ctDNA, show promise for recurrence prediction and treatment monitoring but lack assay standardization. Multiple immune biomarkers demonstrate prognostic value in HCC, and pre-existing immunity characterized by high CD8+ T-cell infiltration and inflammatory gene signatures is associated with improved ICI-based therapy outcomes in exploratory studies. However, these exploratory markers have not been validated for routine selection among HCC regimens. Future directions include prospective validation of composite biomarker panels, standardization of assessment methodologies, and integration of artificial intelligence for TME characterization.