Mechanisms of Resistance and Immune-Related Adverse Events Associated with Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: A Narrative Review.
8 affiliations
- 1Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People's Republic of China.
- 2The Second Clinical Medical College, Kunming Medical University, Kunming, Yunnan, People's Republic of China.
- 3Department of Bone and Joint Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
- 4Department of Hepatobiliary Surgery and Liver Transplantation, The First People's Hospital of Yunnan Province, Kunming, Yunnan, People's Republic of China.
- 5Department of International Healthcare, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People's Republic of China.
- 6Department of Hepatobiliary Surgery, Beihai People's Hospital, Beihai, Guangxi, People's Republic of China.
- 7Department of Surgical Education and Research, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, People's Republic of China.
- 8Yunnan Yunke Bio-Technology Institution, Kunming, Yunnan, People's Republic of China.
Abstract
Immune checkpoint inhibitors (ICIs) have transformed the treatment of hepatocellular carcinoma (HCC), but their clinical benefits are constrained by primary and acquired resistance and immune-related adverse events (irAEs). Understanding the biological processes underlying these outcomes is essential for improving treatment efficacy and safety. This narrative review synthesizes evidence on ICI resistance and irAEs in HCC across tumor-intrinsic, microenvironmental, and systemic dimensions. Primary resistance involves impaired tumor antigen presentation, dysregulated oncogenic signaling, limited immune-cell infiltration, metabolic immunosuppression, and systemic immune dysfunction, with additional influences from the gut microbiota and underlying liver disease. Acquired resistance may involve immunoediting and clonal escape, compensatory inhibitory checkpoint signaling, and treatment-associated immunosuppressive remodeling of the tumor microenvironment. Mechanisms potentially contributing to irAEs include loss of peripheral immune tolerance, T-cell-mediated tissue injury, dysregulated inflammatory cytokine production, antigenic cross-reactivity, and autoantibody-associated immune dysregulation. The strength of evidence varies substantially across these mechanisms: several are supported by experimental HCC models and clinical observations, whereas others remain largely extrapolated from non-HCC settings or lack causal validation. Future priorities include integrating baseline and longitudinal tumor and host immune profiling to develop predictive biomarkers, detect emerging resistance, and identify patients at increased risk of severe toxicity. Prospective HCC-specific studies are needed to determine whether mechanism-guided interventions can improve outcomes. A more precise understanding of antitumor immunity and tissue tolerance may inform individualized strategies that sustain tumor control while preserving liver function and minimizing immune-related toxicity.
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BibTeX
@article{li2026mechanisms,
title = {{Mechanisms of Resistance and Immune-Related Adverse Events Associated with Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: A Narrative Review.}},
author = {Jin Li and Jin-Yi Zhou and Yue Yu and Xing-Ming Chen and Wan-Ling Luo and Yawhan Lakang and Jin-Xiang Zuo and Zi-Sheng Yang and Hao-Bo Xu and Yu-Bo Liang and Qing-Bo Wang and Yu-Kai Li and Li-Ming Shang and Yang Ke},
journal = {Journal of hepatocellular carcinoma},
year = {2026},
month = oct,
doi = {10.2147/jhc.s622555},
url = {https://europepmc.org/article/MED/42960125},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Mechanisms of Resistance and Immune-Related Adverse Events Associated with Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: A Narrative Review.
AU - Jin Li
AU - Jin-Yi Zhou
AU - Yue Yu
AU - Xing-Ming Chen
AU - Wan-Ling Luo
AU - Yawhan Lakang
AU - Jin-Xiang Zuo
AU - Zi-Sheng Yang
AU - Hao-Bo Xu
AU - Yu-Bo Liang
AU - Qing-Bo Wang
AU - Yu-Kai Li
AU - Li-Ming Shang
AU - Yang Ke
PY - 2026
DA - 2026/10/25
JO - Journal of hepatocellular carcinoma
DO - 10.2147/jhc.s622555
UR - https://europepmc.org/article/MED/42960125
AB - Immune checkpoint inhibitors (ICIs) have transformed the treatment of hepatocellular carcinoma (HCC), but their clinical benefits are constrained by primary and acquired resistance and immune-related adverse events (irAEs). Understanding the biological processes underlying these outcomes is essential for improving treatment efficacy and safety. This narrative review synthesizes evidence on ICI resistance and irAEs in HCC across tumor-intrinsic, microenvironmental, and systemic dimensions. Primary resistance involves impaired tumor antigen presentation, dysregulated oncogenic signaling, limited immune-cell infiltration, metabolic immunosuppression, and systemic immune dysfunction, with additional influences from the gut microbiota and underlying liver disease. Acquired resistance may involve immunoediting and clonal escape, compensatory inhibitory checkpoint signaling, and treatment-associated immunosuppressive remodeling of the tumor microenvironment. Mechanisms potentially contributing to irAEs include loss of peripheral immune tolerance, T-cell-mediated tissue injury, dysregulated inflammatory cytokine production, antigenic cross-reactivity, and autoantibody-associated immune dysregulation. The strength of evidence varies substantially across these mechanisms: several are supported by experimental HCC models and clinical observations, whereas others remain largely extrapolated from non-HCC settings or lack causal validation. Future priorities include integrating baseline and longitudinal tumor and host immune profiling to develop predictive biomarkers, detect emerging resistance, and identify patients at increased risk of severe toxicity. Prospective HCC-specific studies are needed to determine whether mechanism-guided interventions can improve outcomes. A more precise understanding of antitumor immunity and tissue tolerance may inform individualized strategies that sustain tumor control while preserving liver function and minimizing immune-related toxicity.
SN - 2253-5969
ER -