J Liver Cancer.  2025 Mar;25(1):9-18. 10.17998/jlc.2024.12.02.

Molecular and immune landscape of hepatocellular carcinoma for therapeutic development

• Suzuki H
• Mishra S
• Paul S
• Hoshida Y

• KMID: 2567060
• DOI: http://doi.org/10.17998/jlc.2024.12.02

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with an estimated 750,000 deaths in 2022. Recent emergence of molecular targeted agents and immune checkpoint inhibitors and their combination therapies have been transforming HCC care, but their prognostic impact in advanced-stage disease remains unsatisfactory. In addition, their application to early-stage disease is still an unmet need. Omics profiling studies have elucidated recurrent and heterogeneously present molecular aberrations involved in pro-cancer tumor (immune) microenvironment that may guide therapeutic strategies. Recurrent aberrations such somatic mutations in TERT promoter and TP53 have been regarded undruggable, but recent studies have suggested that these may serve as new classes of therapeutic targets. HCC markers such as alpha-fetoprotein, glypican-3, and epithelial cell adhesion molecule have also been explored as therapeutic targets. These molecular features may be utilized as biomarkers to guide the application of new approaches as companion biomarkers to maximize therapeutic benefits in patients who are likely to benefit from the therapies, while minimizing unnecessary harm in patients who will not respond. The explosive number of new agents in the pipelines have posed challenges in their clinical testing. Novel clinical trial designs guided by predictive biomarkers have been proposed to enable their efficient and cost-effective evaluation. These new developments collectively facilitate clinical translation of personalized molecular-targeted therapies in HCC and substantially improve prognosis of HCC patients.

Keyword

Hepatocellular carcinoma; Molecular targeted therapy; Clinical trial design; Predictive biomarker

Figure

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  Figure 1. Therapeutic strategies according to molecular and immune landscape of HCC. (A) Molecular subtypes of HCC tumors and associated histological and molecular features. (B) Molecular and cellular targets for approved drugs and therapeutic strategies in development in HCC. CAR-T cells, chimeric antigen receptor T cells; GPC3, glypican-3; AFP, alpha-fetoprotein; EpCAM, epithelial cell adhesion molecule; neoAg, neo antigen; VEGF, vascular endothelial growth factor; FGF, fibroblast growth factor; PDGFβ, platelet-derived growth factor beta; EGF, epidermal growth factor; HGF, hepatocyte growth factor; APC, antigen presenting cell; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; VEGFR, vascular endothelial growth factor receptor; FGFR, fibroblast growth factor receptor; PDGFR, platelet-derived growth factor receptor; EGFR, epidermal growth factor receptor; MET, MET proto-oncogene (hepatocyte growth factor receptor); PD-L1, programmed cell death ligand 1; mTOR, mechanistic target of rapamycin; JAK/STAT, Janus kinase/signal transducer and activator of transcription; MAPK, mitogen-activated protein kinase; PI3K/Akt, phosphatidylinositol 3-kinase/protein kinase B; PD-1, programmed cell death protein 1; CDK, cyclin-dependent kinase; DKK1, dickkopf-1; Rb, retinoblastoma; HCC, hepatocellular carcinoma; TGFβ, transforming growth factor beta; TGFβR, transforming growth factor beta receptor; TERT, telomerase reverse transcriptase.

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  Figure 2. Study designs for biomarker-guided therapeutic clinical trial in HCC. HCC, hepatocellular carcinoma.

Reference

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