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.
Keywords: HCC; atezolizumab; bevacizumab; immunotherapy; liver cell lineages; mechanisms of response and resistance; molecular subtype.
Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.