FCGR2A defines prognostic immune subtypes and drives tumor progression in hepatocellular carcinoma

Deyuan Zhong; Yuxin Liang; Hongtao Yan; Xing Chen; YaHui Chen; Shuoshuo Ma; Yuhao Su; Fei Wang; Xinpei Chen; Qinyan Yang; Zhengwei Leng; Ming Wang; Xiaolun Huang

doi:10.3389/fimmu.2025.1641420

FCGR2A defines prognostic immune subtypes and drives tumor progression in hepatocellular carcinoma

Front Immunol. 2025 Oct 24:16:1641420. doi: 10.3389/fimmu.2025.1641420. eCollection 2025.

Authors

Affiliations

¹ Department of Liver Transplantation Center and Hepato-Biliary-Pancreatic (HBP) Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
² State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macao, Macao SAR, China.
³ Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China.

Abstract

Background: The immunosuppressive nature of the HCC tumor microenvironment limits the effectiveness of current immunotherapeutic strategies. Identifying key immune-related regulators is essential for improving patient stratification and therapeutic outcomes.

Methods: Transcriptomic data from TCGA and GEO datasets were integrated to screen IRDEGs. Functional enrichment, co-expression, and PPI network analyses were performed to explore the biological context. Consensus clustering based on hub gene expression was used to define immune-related molecular subtypes. Immune infiltration characteristics, immune checkpoint expression, TIDE and IPS scores, and predicted immunotherapy responses were compared. FCGR2A expression was validated in clinical HCC tissues by immunohistochemistry and western blotting. In vitro assays evaluated the effects of FCGR2A knockdown on HCC cell proliferation, migration, and invasion.

Results: A total of 21 IRDEGs were identified, among which FCGR2A was consistently upregulated and associated with poor prognosis. Enrichment analysis indicated significant involvement in immune activation and inflammatory signaling pathways. PPI network analysis identified nine hub genes, including FCGR2A. Consensus clustering revealed two distinct immune-related molecular subtypes with marked differences in immune infiltration patterns, immune checkpoint profiles, TIDE and IPS scores. GSEA demonstrated subtype-specific activation of antigen processing, T cell signaling, and inflammatory pathways. Experimental validation confirmed elevated FCGR2A expression in HCC tissues. Functional assays showed that FCGR2A knockdown significantly inhibited HCC cell proliferation, migration, and invasion.

Conclusions: FCGR2A acts as both a prognostic biomarker and an immune regulatory hub in HCC, anchoring a broader gene network that defines immune subtypes and predicts therapeutic responsiveness. Incorporating FCGR2A-based stratification may optimize immunotherapeutic strategies for HCC.

Keywords: FCGR2A; bioinformatics; functional validation; hepatocellular carcinoma; immune subtypes; immunotherapy.

MeSH terms

Biomarkers, Tumor* / genetics
Carcinoma, Hepatocellular* / genetics
Carcinoma, Hepatocellular* / immunology
Carcinoma, Hepatocellular* / metabolism
Carcinoma, Hepatocellular* / mortality
Carcinoma, Hepatocellular* / pathology
Cell Line, Tumor
Cell Movement
Cell Proliferation
Disease Progression
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Liver Neoplasms* / genetics
Liver Neoplasms* / immunology
Liver Neoplasms* / metabolism
Liver Neoplasms* / mortality
Liver Neoplasms* / pathology
Male
Prognosis
Receptors, IgG* / genetics
Receptors, IgG* / immunology
Receptors, IgG* / metabolism
Tumor Microenvironment / genetics
Tumor Microenvironment / immunology

Substances

Receptors, IgG
FCGR2A protein, human
Biomarkers, Tumor