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Updated: Aug 6, 2026
Mass Cytometry Analysis of Systemic and Local Immune Responses in Hepatocellular Carcinoma
Published on: April 25, 2025
Single-cell transcriptomic profiling of immune microenvironment remodeling in unresectable hepatocellular carcinoma
Hai-Feng Zhou1, Bi-Fei Wu1, Wei Ding2
1Department of Interventional Radiology, The First Affiliated Hospital with Nanjing Medical University, No. 300 Guangzhou Road, Nanjing 210029, China.
Background:
The mechanisms underlying immune microenvironment remodeling remain unclear for patients with unresectable hepatocellular carcinoma (uHCC) undergoing transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). This study aims to identify the key features that change following the combination therapy in patients with uHCC.
Methods:
Single-cell transcriptomic profiling was conducted on uHCC samples from the control group, pre-treatment group, and post-treatment group. The Cancer Genome Atlas (TCGA) database was obtained for prognostic analysis. Enriched genes and pathways were identified, and the association and underlying mechanisms of the identified sub-cluster of cells were elucidated in relation to other cellular components.
Results:
A total of 82,687 cells were obtained from seven patients with uHCC. In the pre-treatment group, the CancerCells_1 was associated with epithelial-mesenchymal transition, indicating a poor prognosis, as evidenced by data from 370 HCC patients in TCGA database. In the post-treatment group, a high proportion of macrophages_FOLR2 was observed corresponding to an elevated interferon response signature score and a diminished pro-angiogenic signature score. The exhaustion of CD8+ effector T cell (CD8Teff) was mitigated by downregulating the notable expression of BHLHE40 and CXCL13. Following treatment, there was an increase in liver sinusoidal endothelial cell (LSEC), while both angiogenesis and TGF-β pathway scores were reduced. Notable changes were observed in the interactions across different cells, particularly concerning the key signatures of LGALS9_HAVCR2, CSF1_CSF1R, and VEGFB_FLT1.
Conclusion:
After combined treatment, uHCC patients were characterized by macrophages_FOLR2, CD8Teff, and LSEC, indicating a remodeling of the immune microenvironment.
Insights
This study reveals how combination therapy remodels the immune microenvironment in unresectable hepatocellular carcinoma (uHCC). Key changes include altered macrophage and T cell populations, suggesting new therapeutic strategies for uHCC patients.
Area of Science:
- Immunology
- Oncology
- Genomics
Background:
- Immune microenvironment remodeling mechanisms in unresectable hepatocellular carcinoma (uHCC) undergoing combined transarterial chemoembolization (TACE), tyrosine kinase inhibitors (TKIs), and immune checkpoint inhibitors (ICIs) are not well understood.
- Identifying key cellular and molecular changes post-combination therapy is crucial for improving treatment efficacy in uHCC.
Purpose of the Study:
- To investigate the alterations in the immune microenvironment of uHCC patients following combination therapy (TACE + TKIs + ICIs).
- To identify specific cell populations, gene expression patterns, and pathway changes associated with treatment response.
Main Methods:
- Single-cell transcriptomic profiling of uHCC tumor samples from pre-treatment and post-treatment groups.
- Utilized The Cancer Genome Atlas (TCGA) database for prognostic correlation.
- Analyzed enriched genes, pathways, and cell-cell interactions to elucidate treatment-induced changes.
Main Results:
- Pre-treatment samples showed CancerCells_1 associated with poor prognosis (epithelial-mesenchymal transition).
- Post-treatment samples exhibited increased macrophages expressing FOLR2, elevated interferon response, and reduced pro-angiogenic signatures.
- CD8+ effector T cell (CD8Teff) exhaustion was reduced, with decreased BHLHE40 and CXCL13 expression. Liver sinusoidal endothelial cell (LSEC) populations increased, while angiogenesis and TGF-β pathways were downregulated.
Conclusions:
- Combination therapy significantly remodels the immune microenvironment in uHCC.
- Key cellular players post-treatment include macrophages_FOLR2, CD8Teff, and LSEC.
- These findings provide insights into treatment response mechanisms and potential therapeutic targets for uHCC.
