Targeted Therapies for Hepatocellular Carcinoma

The overarching landscape of targeted treatments for hepatocellular carcinoma encompasses agents directed against key molecular drivers of tumour proliferation, angiogenesis and immune evasion. First-line small-molecule inhibitors of tyrosine kinases, notably sorafenib and lenvatinib, have yielded modest survival benefits by blocking pathways such as vascular endothelial growth factor receptor, platelet-derived growth factor receptor and fibroblast growth factor receptor. Second-line options including regorafenib, cabozantinib and ramucirumab have extended this paradigm by overcoming acquired resistance mechanisms and targeting additional kinases or the VEGF axis. More recently, monoclonal antibodies that inhibit immune checkpoints—principally the programmed cell death-1 receptor (PD-1), its ligand (PD-L1) and CTLA-4—have transformed therapeutic approaches by reactivating cytotoxic T-cell responses within the immunosuppressive tumour microenvironment. Combination regimens that pair anti-angiogenic agents with immune checkpoint inhibitors or dual checkpoint blockade have demonstrated synergistic activity in phase II and III trials. Neoadjuvant and adjuvant applications of these combinations are under evaluation to achieve greater pathological regression and reduce relapse after surgical resection. Efforts to identify predictive biomarkers, such as circulating tumour DNA and patterns of immune cell infiltration, aim to refine patient selection and monitor response in real time. Resistance mechanisms—ranging from activation of alternative signalling cascades to immunoregulatory adaptation—remain a challenge and are driving ongoing research into novel targets and combination strategies with locoregional therapies such as transarterial chemoembolisation and radiotherapy.

Research from Nature Portfolio

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Targeted Therapies for Hepatocellular Carcinoma publication trend

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

Technical terms

Tyrosine kinase inhibitor (TKI): A small molecule that binds to and inhibits tyrosine kinase enzymes involved in tumour growth and angiogenesis.

Immune checkpoint inhibitor (ICI): A monoclonal antibody targeting regulatory pathways (such as PD-1, PD-L1 or CTLA-4) to restore T-cell–mediated anti-tumour immunity.

Major pathological response (MPR): A postoperative finding of at least 70 per cent tumour regression in the resected specimen following neoadjuvant therapy.

Pathological complete response (pCR): The absence of viable tumour cells in surgical specimens after neoadjuvant treatment.

Circulating tumour DNA (ctDNA): Fragments of tumour-derived DNA released into the bloodstream used for non-invasive biomarker analysis.

References

1. Targeted therapy for hepatocellular carcinoma. Signal Transduction and Targeted Therapy (2020).
2. Angiogenesis and immune checkpoint inhibitors as therapies for hepatocellular carcinoma: current knowledge and future research directions. Journal for ImmunoTherapy of Cancer (2019).
3. Molecular Bases of Drug Resistance in Hepatocellular Carcinoma. Cancers (2020).
4. Pathological response following neoadjuvant immune checkpoint inhibitors in patients with hepatocellular carcinoma: a cross-trial, patient-level analysis. The Lancet Oncology (2024).
5. Efficacy and safety of camrelizumab plus apatinib during the perioperative period in resectable hepatocellular carcinoma: a single-arm, open label, phase II clinical trial. Journal for ImmunoTherapy of Cancer (2022).
6. Regorafenib combined with PD1 blockade increases CD8 T-cell infiltration by inducing CXCL10 expression in hepatocellular carcinoma. Journal for ImmunoTherapy of Cancer (2020).
7. Combinational Immunotherapy for Hepatocellular Carcinoma: Radiotherapy, Immune Checkpoint Blockade and Beyond. Frontiers in Immunology (2020).