Systemic Therapy for Advanced Hepatocellular Carcinoma

Advanced hepatocellular carcinoma (HCC) presents a formidable challenge due to underlying liver dysfunction, tumour heterogeneity and intrinsic resistance mechanisms. Systemic therapy has evolved from the era of sorafenib, the first approved multi-targeted tyrosine kinase inhibitor (TKI), to a diverse armamentarium that includes second-generation TKIs, monoclonal antibodies against angiogenic factors and immune checkpoint inhibitors. First-line options now include lenvatinib and the combination of an anti-PD-L1 agent with vascular endothelial growth factor (VEGF) blockade, which have demonstrated superior overall survival and progression-free survival compared with sorafenib. In the second line, regorafenib, cabozantinib and ramucirumab offer benefit for patients intolerant of or refractory to first-line agents. Immune checkpoint blockade targeting PD-1 or PD-L1 has moved into routine practice, often in combination with antiangiogenic drugs to reshape the tumour microenvironment and enhance effector T-cell infiltration. Novel approaches such as oncolytic virotherapy and pathway-directed agents against tumour-driving cascades further expand systemic options. Despite these advances, the median survival for advanced HCC remains under two years, underscoring the need for biomarkers to guide patient selection and the development of rational combination regimens that overcome adaptive resistance.

Research from Nature Portfolio

Recent studies have uncovered a prominent role for the Hedgehog signalling cascade in HCC pathogenesis. Comprehensive analysis of resected human specimens and in silico datasets has revealed high expression and module connectivity of key Hedgehog components, including PTCH1 and GLI transcription factors, in aggressive tumours. Functional assays in primary HCC cultures indicate that pharmacological inhibition of the Hedgehog pathway enhances chemosensitivity, particularly to agents with antiangiogenic properties. This work establishes aberrant Hedgehog signalling as both a prognostic marker and a targetable vulnerability, suggesting that the inclusion of pathway inhibitors could refine systemic regimens and improve response rates in selected patient subgroups.

Systemic Therapy for Advanced Hepatocellular Carcinoma publication trend

The graph below shows the total number of articles in systemic therapy for advanced hepatocellular carcinoma across all publications each year (not limited to Nature Index journals).

Technical terms

Tyrosine kinase inhibitor (TKI): A small-molecule drug that blocks the enzymatic activity of receptor or non-receptor tyrosine kinases involved in tumour growth and angiogenesis.

Immune checkpoint inhibitor: A class of monoclonal antibodies that releases inhibitory brakes on T cells, enhancing anti-tumour immunity by targeting proteins such as PD-1 or PD-L1.

Hedgehog pathway: A developmental signalling cascade involving ligands (e.g. Sonic Hedgehog), receptors (PTCH1) and GLI transcription factors, which can drive tumour cell proliferation when aberrantly activated.

Oncolytic virotherapy: A therapeutic strategy that employs viruses engineered to selectively infect and lyse cancer cells, while stimulating systemic immune responses against tumours.

Tumour microenvironment: The complex milieu of stromal cells, extracellular matrix, blood vessels and immune infiltrates that surrounds and influences tumour behaviour and treatment response.

References

1. Enhancing immune response and survival in hepatocellular carcinoma with novel oncolytic Jurona virus and immune checkpoint blockade. Molecular Therapy Oncology (2024).
2. Hedgehog components are overexpressed in a series of liver cancer cases. Scientific Reports (2024).
3. Targeted Therapy for Hepatocellular Carcinoma: Old and New Opportunities. Cancers (2022).