Molecular subtypes of hepatocellular carcinoma linked to liver cell lineages and clinical outcomes of combination immunotherapy
Understanding the biology and clinical relevance of disease heterogeneity in hepatocellular carcinoma (HCC) is important for guiding therapeutic strategies. Through multi-omics and in situ analyses in three independent cohorts of patients with advanced HCC including GO30140 phase 1b and IMbrave150 phase 3 trials, we identified three robust molecular subtypes of HCC, i.e., cholangiocyte-like, progenitor-like, and hepatocyte-like, based on their association with different liver epithelial cell lineages. These subtypes showed distinct tumor cell-intrinsic and extrinsic features, including different immune contextures, and importantly an association with clinical response to atezolizumab plus bevacizumab combination immunotherapy. In a humanized HCC xenograft mouse model recapitulating the GPC3-high progenitor-like subtype, a GPC3/CD3 bispecific antibody elicited strong antitumor activity mediated by intratumoral recruitment and activation of T cells. Our study provides biological insights into HCC heterogeneity and potential strategies for targeting subtype-specific vulnerabilities.
Authors
- Takahiro Ishiguro (ORCID: https://orcid.org/0000-0001-5618-2710)
- Yinghui Guan (ORCID: https://orcid.org/0000-0003-1801-8332)
- Junko Shinozuka (ORCID: https://orcid.org/0009-0002-3380-0760)
- Edward Cha (ORCID: https://orcid.org/0000-0001-8172-0656)
- Christopher Cotter
- Gabriele Dietmann
- Hartmut Koeppen (ORCID: https://orcid.org/0000-0003-0923-3110)
- Joshua D. Webster (ORCID: https://orcid.org/0000-0002-0014-1685)
- Michael A. Cannarile (ORCID: https://orcid.org/0000-0001-6062-5588)
- Josep Maria Llovet (ORCID: https://orcid.org/0000-0003-0547-2667)
- Stephen P. Hack (ORCID: https://orcid.org/0000-0002-0640-5709)
- Yuji Sano (ORCID: https://orcid.org/0000-0003-3714-4983)
- Habib Hamidi (ORCID: https://orcid.org/0000-0003-0196-9852)
- Alexander R. Abbas (ORCID: https://orcid.org/0000-0003-2600-810X)
- Richard S. Finn (ORCID: https://orcid.org/0000-0003-2494-2126)
- Yoko Kayukawa (ORCID: https://orcid.org/0009-0003-8848-2840)
- Natascha Rieder (ORCID: https://orcid.org/0000-0002-2921-2280)
- Andrew X. Zhu (ORCID: https://orcid.org/0000-0003-4873-5033)
- Yulei Wang (ORCID: https://orcid.org/0000-0002-9057-9786)
- Shan Lu (ORCID: https://orcid.org/0000-0002-9756-7198)
- Yumiko Azuma (ORCID: https://orcid.org/0000-0002-3282-0703)
- Susan Jain (ORCID: https://orcid.org/0000-0003-3491-1526)
- Alekhya Pochiraju
Institutions
- Roche (Switzerland) (CH)
- University of California, Los Angeles (US)
- Breast Cancer Research Foundation (US)
- Roche Pharma AG (Germany) (DE)
- Chugai Pharma (United States) (US)
- CS Diagnostics (DE)
- Center for Cancer Research (US)
- UCLA Jonsson Comprehensive Cancer Center
- Sunesis (United States) (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-11-28
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102473
- Citations
- 1
- Primary Topic
- Hepatocellular Carcinoma Treatment and Prognosis
- Type
- article
- Field-Weighted Citation Impact
- 1.32