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.