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Clin. Mol. Hepatol., Oct 27 2025, | https://doi.org/10.3350/cmh.2025.0792 Integrative Multi-Omics Profiling Identifies Infiltrative HCC as an Immunotherapy-Resistant Subtype with Distinct Molecular Features

Won Suk Lee ^{1 †}, Seonjeong Woo ^{2 †}, Sung Hwan Lee ^{3 †}, Gae Hoon Jo ², Ilhwan Kim ⁴, Hyeyeong Kim ⁵, Chansik An ⁶, Sanghoon Jung ⁶, Gwangil Kim ⁷, Haeyoun Kang ⁷, Beodeul Kang¹, Jung Sun Kim ¹, Ho Yeong Lim ¹, Incheon Kang ³, Hannah Yang ¹, So Jung Kong ¹, Dahyeon Son ¹, Dong Jun Shin ², Woo Young Kwon ³, Da-Yeon Lee ², Ju-Seog Lee ⁸, Junho Park ⁹, Youngsoo Kim¹⁰, Sohyun Hwang ^{7 *}, Chan Kim ^{1 *}, Hong Jae Chon ^{1 *}

¹Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea.
²Department of Life Science, CHA University, Seongnam, Korea.
³Department of Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea.
⁴Division of Oncology, Department of Internal Medicine, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea.
⁵Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea.
⁶Department of Radiology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea.
⁷Department of Pathology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea.
⁸Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁹Department of Medical Science, CHA University School of Medicine, Seongnam, Korea.
¹⁰Advanced Omics Center, CHA Bundang Medical Center, Seongnam, Korea.

^†These authors contributed equally
^*Corresponding authors: correspondence to Sohyun Hwang, Chan Kim or Hong Jae Chon

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.

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