Immune and Circulating Biomarkers in Hepatocellular Carcinoma: Prognostic and Predictive Relevance for Immunotherapy
7 affiliations
- 1Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA
- 2Faculty of Medicine, Istanbul Arel University, Büyükçekmece 34010, Türkiye
- 3Department of Medicine, Huntsville Hospital Health System, Decatur Morgan Hospital, Decatur, AL 35601, USA
- 4Faculty of Medicine, Yeditepe University, Istanbul 34755, Türkiye
- 5Internal Medicine, Oregon Health & Science University, Portland, OR 97239, USA
- 6Division of Hematology and Oncology, UC San Diego Health System, San Diego, CA 92123, USA
- 7Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL 35233, USA
Abstract
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.
Related
- Early Assessment of Circulating Tumor Cells and Their PD-L1 Expression as Predictive Biomarkers in Metastatic Non-Small Cell Lung Cancer Patients Treated with Immunotherapy: An Exploratory Study
- Correlation between circulating tumor cell levels and tumor response in patients with advanced hepatocellular carcinoma undergoing immunotherapy and molecular targeted therapy
- Strategies of mechanical adaptations of circulating tumor cells and properties of their cellular microenvironment have predictive and prognostic biomarker value
- Identification of CRF-related molecular subtypes and a prognostic CRRS model in glioma: insights into immunotherapy response prediction and candidate biomarkers
- Identification of hepatitis B virus-associated membrane proteins as prognostic biomarkers for hepatocellular carcinoma based on retrospective analysis of integrated membrane proteomics
BibTeX
@article{sidhom2026immune,
title = {{Immune and Circulating Biomarkers in Hepatocellular Carcinoma: Prognostic and Predictive Relevance for Immunotherapy}},
author = {Fady Sidhom and Emin Karabiber and Rafik ElBeblawy and Atakan Babagiray and Timmothy Yacoub and Bassel El-Rayes and Mehmet Akce},
journal = {Cancers},
year = {2026},
month = oct,
doi = {10.3390/cancers18213429},
url = {https://www.mdpi.com/2072-6694/18/21/3429},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Immune and Circulating Biomarkers in Hepatocellular Carcinoma: Prognostic and Predictive Relevance for Immunotherapy
AU - Fady Sidhom
AU - Emin Karabiber
AU - Rafik ElBeblawy
AU - Atakan Babagiray
AU - Timmothy Yacoub
AU - Bassel El-Rayes
AU - Mehmet Akce
PY - 2026
DA - 2026/10/23
JO - Cancers
DO - 10.3390/cancers18213429
UR - https://www.mdpi.com/2072-6694/18/21/3429
AB - 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.
SN - 2072-6694
ER -