Integrative Multi-omics Profiling Identifies Infiltrative Hepatocellular Carcinoma as an Immunotherapy-Resistant Subtype With Distinct Molecular Features

Authors

Won Suk Lee
Seonjeong Woo
Sung Hwan Lee
Gae Hoon Jo
Ilhwan Kim
Hyeyeong Kim
Chansik An
Sanghoon Jung
Gwangil Kim
Haeyoun Kang
Beodeul Kang
Jung Sun Kim
Ho Yeong Lim
Incheon Kang
Hannah Yang
So Jung Kong
Dahyeon Son
Dong Jun Shin
Woo Young Kwon
Da-Yeon Lee
Ju-Seog Lee
Junho Park
Youngsoo Kim
Sohyun Hwang
Chan Kim
Hong Jae Chon

Language

English

Publication Date

1-1-2026

Journal

Clinical and Molecular Hepatology

DOI

10.3350/cmh.2025.0792

PMID

41146520

PMCID

PMC12835808

PubMedCentral® Posted Date

10-27-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Background/aims: Hepatocellular carcinoma (HCC) exhibits substantial morphological and biological heterogeneity. Clinical and molecular relevance of the infiltrative subtype remains poorly defined in the context of cancer immunotherapy. We aimed to evaluate the prognostic impact and molecular features of infiltrative HCC in patients treated with first-line atezolizumab plus bevacizumab (Ate/Bev).

Methods: We included 307 patients with advanced HCC treated with Ate/Bev and classified them into four gross morphological types based on imaging. Multi-omics profiling was conducted on tumor samples. Type IV infiltrative signature was derived and externally validated using five independent HCC cohorts, including IMbrave150.

Results: Infiltrative morphology, encompassing pure and mixed forms, was present in 42.7% of advanced HCC and associated with advanced disease features and compromised liver function. Patients with type IV infiltrative HCC showed lowest objective response rate (14.6%) and worst progression-free (median, 2.8 months) and overall survival (median, 7.1 months). Infiltrative morphology remained an independent predictor of poor outcomes after multivariable adjustment for confounders, including intrahepatic tumor extent. Genomic profiling revealed enriched TP53 and ATM loss-of-function mutations in type IV infiltrative HCC. Transcriptomic and proteomic analyses identified consistent activation of tumor proliferation, epithelial-mesenchymal transition, TGF-β signaling, and immunosuppressive pathways in type IV infiltrative HCC. Type IV infiltrative signature was significantly associated with poor survival across external datasets and retained independent prognostic value.

Conclusions: Infiltrative HCC is a clinically aggressive and molecularly distinct subtype of advanced HCC. Morphological classification and type IV infiltrative signatures may guide risk stratification and therapeutic decision-making in advanced HCC treated with immunotherapy.

Keywords

Humans, Carcinoma, Hepatocellular, Liver Neoplasms, Male, Female, Middle Aged, Aged, Immunotherapy, Antibodies, Monoclonal, Humanized, Bevacizumab, Prognosis, Tumor Suppressor Protein p53, Drug Resistance, Neoplasm, Gene Expression Profiling, Multiomics, Advanced hepatocellular carcinoma, Immunotherapy, Gross classification, Infiltrative morphology, Multiomics analysis

Published Open-Access

yes

Recommended Citation

Lee, Won Suk; Woo, Seonjeong; Lee, Sung Hwan; et al., "Integrative Multi-omics Profiling Identifies Infiltrative Hepatocellular Carcinoma as an Immunotherapy-Resistant Subtype With Distinct Molecular Features" (2026). Faculty, Staff and Student Publications. 6055.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6055