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  • Review Article
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Precision models in hepatocellular carcinoma

Nature Reviews Gastroenterology & Hepatology volume 22, pages 191–205 (2025)Cite this article

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Abstract

Hepatocellular carcinoma (HCC) represents a global health challenge, and ranks among one of the most prevalent and deadliest cancers worldwide. Therapeutic advances have expanded the treatment armamentarium for patients with advanced HCC, but obstacles remain. Precision oncology, which aims to match specific therapies to patients who have tumours with particular features, holds great promise. However, its implementation has been hindered by the existence of numerous ‘HCC influencers’ that contribute to the high inter-patient heterogeneity. HCC influencers include tumour-related characteristics, such as genetic alterations, immune infiltration, stromal composition and aetiology, and patient-specific factors, such as sex, age, germline variants and the microbiome. This Review delves into the intricate world of HCC, describing the most innovative model systems that can be harnessed to identify precision and/or personalized therapies. We provide examples of how different models have been used to nominate candidate biomarkers, their limitations and strategies to optimize such models. We also highlight the importance of reproducing distinct HCC influencers in a flexible and modular way, with the aim of dissecting their relative contribution to therapy response. Next-generation HCC models will pave the way for faster discovery of precision therapies for patients with advanced HCC.

Key points

  • Precision therapies in hepatocellular carcinoma (HCC) are difficult to establish owing to high inter-patient heterogeneity.

  • Several factors, or ‘HCC influencers’, contribute to HCC inter-patient heterogeneity.

  • Current in vitro and in vivo models recapitulate some but not all of the HCC influencers.

  • Improvements in the establishment success rate of in vitro HCC models could help the implementation of precision or personalized therapies for HCC, but they might not be ideal for immunotherapy studies.

  • Next-generation in vivo models, recapitulating multiple HCC influencers as well as including human cellular components, could help the implementation of precision therapies for HCC.

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Fig. 1: Pipeline for the discovery of precision and personalized therapies in hepatocellular carcinoma.
Fig. 2: HCC influencers.

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Acknowledgements

S.P.M. and A.L. were supported by NIH grant RO1CA251155 awarded to the University of Pittsburgh and Icahn School of Medicine at Mount Sinai.

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Authors and Affiliations

  1. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Marina Barcena-Varela & Amaia Lujambio

  2. Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Marina Barcena-Varela & Amaia Lujambio

  3. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Marina Barcena-Varela & Amaia Lujambio

  4. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Satdarshan P. Monga

  5. Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Satdarshan P. Monga

  6. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Satdarshan P. Monga

  7. Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Satdarshan P. Monga

  8. Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Amaia Lujambio

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A.L. researched the data for the article, made a substantial contribution to the discussion of content, wrote the article, and reviewed and/or edited the manuscript before submission. M.B.-V. researched the data for the article. S.P.M. made a substantial contribution to the discussion of content.

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Correspondence to Amaia Lujambio.

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Barcena-Varela, M., Monga, S.P. & Lujambio, A. Precision models in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 22, 191–205 (2025). https://doi.org/10.1038/s41575-024-01024-w

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