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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

Molecular Mechanisms of Therapeutic Resistance in Hepatocellular Carcinoma

  • Karen Hoi Lam Li1
  • Frances Sun1
  • Samuel Chan1,2
  • Roland Ching Yu Leung1
  • Bryan Cho Wing Li1,2
  • Jeffrey Sum Lung Wong1
  • Tiffany Hoi Wing Fung1
  • Jenny Wai Yan Lo1
  • Alvin Hoi Wai Chan1
  • Thomas Yau1,2
  1. 1Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
  2. 2Centre of Cancer Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
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Abstract

Hepatocellular carcinoma (HCC) remains a major global health burden, and therapeutic resistance continues to limit the benefit from systemic treatment. Despite advances in systemic therapies, including immune checkpoint inhibitor-based combinations, antiangiogenic agents, and multitargeted tyrosine kinase inhibitors for patients with advanced HCC, primary non-response and acquired resistance are common. This review summarizes the mechanisms that underlie resistance to contemporary HCC therapies, including tumour heterogeneity, molecular pathway rewiring and crosstalk, tumour microenvironment and immune escape, epigenetic alterations, epithelial-to-mesenchymal transition, and cancer stem cell expansion. We discuss how these mechanisms limit the efficacy of current doublet and triplet regimens, and why biologically rational combinations do not consistently translate into clinical benefit. Emerging strategies to overcome resistance, including biomarker-enriched trial designs and liquid biopsy are also discussed. A deeper integration of mechanistic insights with translational biomarkers will be essential to improve treatment durability and clinical outcomes for patients with HCC.

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Cite

BibTeXRIS
BibTeX
@article{li2026molecular,
  title = {{Molecular Mechanisms of Therapeutic Resistance in Hepatocellular Carcinoma}},
  author = {Karen Hoi Lam Li and Frances Sun and Samuel Chan and Roland Ching Yu Leung and Bryan Cho Wing Li and Jeffrey Sum Lung Wong and Tiffany Hoi Wing Fung and Jenny Wai Yan Lo and Alvin Hoi Wai Chan and Thomas Yau},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = oct,
  doi = {10.3390/ijms27219690},
  url = {https://www.mdpi.com/1422-0067/27/21/9690},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Molecular Mechanisms of Therapeutic Resistance in Hepatocellular Carcinoma
AU  - Karen Hoi Lam Li
AU  - Frances Sun
AU  - Samuel Chan
AU  - Roland Ching Yu Leung
AU  - Bryan Cho Wing Li
AU  - Jeffrey Sum Lung Wong
AU  - Tiffany Hoi Wing Fung
AU  - Jenny Wai Yan Lo
AU  - Alvin Hoi Wai Chan
AU  - Thomas Yau
PY  - 2026
DA  - 2026/10/29
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27219690
UR  - https://www.mdpi.com/1422-0067/27/21/9690
AB  - Hepatocellular carcinoma (HCC) remains a major global health burden, and therapeutic resistance continues to limit the benefit from systemic treatment. Despite advances in systemic therapies, including immune checkpoint inhibitor-based combinations, antiangiogenic agents, and multitargeted tyrosine kinase inhibitors for patients with advanced HCC, primary non-response and acquired resistance are common. This review summarizes the mechanisms that underlie resistance to contemporary HCC therapies, including tumour heterogeneity, molecular pathway rewiring and crosstalk, tumour microenvironment and immune escape, epigenetic alterations, epithelial-to-mesenchymal transition, and cancer stem cell expansion. We discuss how these mechanisms limit the efficacy of current doublet and triplet regimens, and why biologically rational combinations do not consistently translate into clinical benefit. Emerging strategies to overcome resistance, including biomarker-enriched trial designs and liquid biopsy are also discussed. A deeper integration of mechanistic insights with translational biomarkers will be essential to improve treatment durability and clinical outcomes for patients with HCC.
SN  - 1422-0067
ER  -