Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Mechanisms of Action, Therapeutic Efficacy, and Emerging Combination Strategies

Mingqian Gao

doi:10.54254/2753-8818/2025.LD25961

Theoretical and Natural ScienceOpen access

Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Mechanisms of Action, Therapeutic Efficacy, and Emerging Combination Strategies

Research Article

Open Access

Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Mechanisms of Action, Therapeutic Efficacy, and Emerging Combination Strategies

Mingqian Gao ^1*

¹ Johnathan Academy

^*Corresponding author: gaomingqiangmq@outlook.com

Published on 13 August 2025

TNS Vol.122

ISSN (Print): 2753-8826

ISSN (Online): 2753-8818

ISBN (Print): 978-1-80590-269-0

ISBN (Online): 978-1-80590-270-6

Download Cover

Abstract

Over the past decade, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of hepatocellular carcinoma (HCC) at the systemic level. This review analyzes 210 studies (2015–2024) to trace the progression from initial PD-1 blockade trials to modern multi-agent protocols, emphasizing the transformation of HCC’s immune-excluded milieu into one that fosters sustained antitumor activity. Mechanistically, pathways involving PD-1/PD-L1, CTLA-4, LAG-3, and TIM-3 induce T-cell dysfunction, hinder neoantigen recognition, and attract immunosuppressive macrophages. ICIs counteract these effects, revitalizing cytotoxic T-cell migration and diversifying T-cell receptor profiles. Pooled data from phase II/III trials indicate monotherapy response rates of 14–30%, increasing to 27–46% with combinations such as atezolizumab/bevacizumab or durvalumab/tremelimumab. However, these regimens are accompanied by higher-grade adverse events (25–37%). Challenges such as inconsistent biomarker expression, loss of interferon-γ signaling-induced resistance, and overlapping toxicities persist. To address these, the author suggests: (1) multi-parameter biomarker models combining PD-L1, TMB, and circulating CD8+ Ki-67 levels; (2) staggered dosing to separate ICI initiation from anti-angiogenic therapy; and (3) pharmacovigilance systems to track delayed toxicities and tailor treatment withdrawal.

Keywords:

immune checkpoint, hepatocellular carcinoma, combination therapy, PD-1/PD-L1, drug resistance

View PDF

References

[1]. Lou, S., Cao, Z., Chi, W., Wang, X., Feng, M., Lin, L., Ding, Y., Liu, K., Qu, L., Zhao, G., Bao, S. and Wang, H. (2023) The safety concerns regarding immune checkpoint inhibitors in liver cancer patients rising mainly from CHB. Frontiers in Pharmacology, 14, 1164309.

[2]. Donne, R. and Lujambio, A. (2023) The liver cancer immune microenvironment: Therapeutic implications for hepatocellular carcinoma. Hepatology, 77, 1773-1796.

[3]. Zhang, J., Hu, C., Xie, X., Qi, L., Li, C. and Li, S. (2023) Immune Checkpoint Inhibitors in HBV-Caused Hepatocellular Carcinoma Therapy. Vaccines, 11, 614.

[4]. Fu, J., Li, W. Z., McGrath, N. A., Lai, C. W., Brar, G., Xiang, Y. Q., and Xie, C. (2021) Immune Checkpoint Inhibitor Associated Hepatotoxicity in Primary Liver Cancer Versus Other Cancers: A Systematic Review and Meta-Analysis. Frontiers in Oncology, 11, 650292.

[5]. Jeng, L.B., Wang, J. and Teng, C.F. (2024) Predictive Biomarkers of Immune Checkpoint Inhibitor-Based Mono- and Combination Therapies for Hepatocellular Carcinoma. Journal of Cancer, 15, 484-493.

[6]. Cheng, L., Chen, L., Shi, Y., Gu, W., Ding, W., Zheng, X., Liu, Y., Jiang, J. and Zheng, Z. (2024) Efficacy and safety of bispecific antibodies vs. immune checkpoint blockade combination therapy in cancer: a real-world comparison. Molecular Cancer, 23, 77.

[7]. Wang, S.J., Dougan, S.K. and Dougan, M. (2023) Immune mechanisms of toxicity from checkpoint inhibitors. Trends in Cancer, 9, 543-553.

[8]. Lao, Y., Shen, D., Zhang, W., He, R. and Jiang, M. (2022) Immune Checkpoint Inhibitors in Cancer Therapy- How to Overcome Drug Resistance? Cancers, 14, 3575.

[9]. Wang, Y., Li, J. and Xia, L. (2023) Plant-derived natural products and combination therapy in liver cancer. Frontiers in Oncology, 13, 1116532.

[10]. Ju, F., Wang, D., Huang, L., Jiang, C., Gao, C., Xiong, C. and Zhai, G. (2023) Progress of PD-1/PD-L1 signaling in immune response to liver transplantation for hepatocellular carcinoma. Frontiers in Immunology, 14, 1227756.

References

[2]. Donne, R. and Lujambio, A. (2023) The liver cancer immune microenvironment: Therapeutic implications for hepatocellular carcinoma. Hepatology, 77, 1773-1796.

[3]. Zhang, J., Hu, C., Xie, X., Qi, L., Li, C. and Li, S. (2023) Immune Checkpoint Inhibitors in HBV-Caused Hepatocellular Carcinoma Therapy. Vaccines, 11, 614.

[7]. Wang, S.J., Dougan, S.K. and Dougan, M. (2023) Immune mechanisms of toxicity from checkpoint inhibitors. Trends in Cancer, 9, 543-553.

[8]. Lao, Y., Shen, D., Zhang, W., He, R. and Jiang, M. (2022) Immune Checkpoint Inhibitors in Cancer Therapy- How to Overcome Drug Resistance? Cancers, 14, 3575.

[9]. Wang, Y., Li, J. and Xia, L. (2023) Plant-derived natural products and combination therapy in liver cancer. Frontiers in Oncology, 13, 1116532.

Cite this article

Gao,M. (2025). Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Mechanisms of Action, Therapeutic Efficacy, and Emerging Combination Strategies. Theoretical and Natural Science,122,13-19.

Data availability

The datasets used and/or analyzed during the current study will be available from the authors upon reasonable request.

About volume

Volume title: Proceedings of ICBioMed 2025 Symposium: Computational Modelling and Simulation for Biology and Medicine

ISBN: 978-1-80590-269-0(Print) / 978-1-80590-270-6(Online)

Editor: Alan Wang, Roman Bauer

Conference website: https://2025.icbiomed.org/london.html

Conference date: 19 September 2025

Series: Theoretical and Natural Science

Volume number: Vol.122

ISSN: 2753-8818(Print) / 2753-8826(Online)

© 2024 by the author(s). Licensee EWA Publishing, Oxford, UK. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. Authors who publish this series agree to the following terms:

1. Authors retain copyright and grant the series right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this series.

2. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the series's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this series.

3. Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See Open access policy for details).