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Updated: Jun 27, 2026
Generation and Single-Cell Transcriptomic Analysis of Hepatocellular Carcinoma Organoids following Drug Treatment
Published on: May 26, 2026
ABHD17C regulates the efficacy of lenvatinib in suppressing hepatocellular carcinoma
Linpei Wang1, Jiawei Wang1, Xiaoqiu Ma2
1Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.
Introduction:
Lenvatinib is a first-line therapy for hepatocellular carcinoma (HCC), but its clinical efficacy is limited by drug resistance. ABHD17C, a depalmitoylation enzyme involved in HCC progression, has not been investigated in lenvatinib response. This study aimed to determine whether ABHD17C regulates the anti-tumor efficacy of lenvatinib in HCC.
Methods:
Published single-cell RNA sequencing (scRNA-seq) data were analyzed to characterize ABHD17C expression in the HCC tumor microenvironment. Functional assays were performed in HCC cell lines to evaluate the effects of lenvatinib and ABHD17C modulation. The findings were validated using HCC xenograft mouse models and patient-derived tumor organoids.
Results:
scRNA-seq analysis showed that ABHD17C is associated with an immunosuppressive tumor microenvironment characterized by reduced CD8⁺ T cell infiltration, increased T cell exhaustion, and abnormal intercellular communication. In vitro, lenvatinib inhibited proliferation, migration, and invasion while inducing apoptosis and cell cycle arrest in HCC cells. These effects were significantly attenuated by ABHD17C overexpression but enhanced by ABHD17C depletion. In vivo, ABHD17C-overexpressing xenografts were less responsive to lenvatinib, exhibiting increased tumor growth and reduced apoptosis. Similarly, in patient-derived organoids, ABHD17C overexpression diminished lenvatinib efficacy. Notably, lenvatinib reduced ABHD17C expression in organoids, suggesting potential feedback regulation.
Conclusion:
ABHD17C promotes an immunosuppressive tumor microenvironment and attenuates the anti-tumor effects of lenvatinib in HCC. Targeting ABHD17C may represent a potential strategy to enhance lenvatinib sensitivity and improve therapeutic outcomes.
Insights
ABHD17C promotes an immunosuppressive tumor microenvironment, limiting lenvatinib
Area of Science:
- Hepatocellular Carcinoma (HCC) Research
- Tumor Microenvironment Immunology
- Drug Resistance Mechanisms
Background:
- Lenvatinib is a first-line treatment for hepatocellular carcinoma (HCC).
- Drug resistance limits lenvatinib's clinical efficacy in HCC.
- The role of ABHD17C, a depalmitoylation enzyme, in lenvatinib response is unknown.
Purpose of the Study:
- To investigate the role of ABHD17C in regulating lenvatinib's anti-tumor efficacy in HCC.
- To determine if ABHD17C influences the tumor microenvironment in HCC.
- To explore ABHD17C as a potential therapeutic target for overcoming lenvatinib resistance.
Main Methods:
- Analysis of published single-cell RNA sequencing (scRNA-seq) data to assess ABHD17C expression in the HCC tumor microenvironment.
- In vitro functional assays in HCC cell lines to evaluate lenvatinib and ABHD17C modulation effects.
- Validation using HCC xenograft mouse models and patient-derived tumor organoids.
Main Results:
- ABHD17C correlates with an immunosuppressive HCC tumor microenvironment, characterized by reduced CD8+ T cell infiltration and increased T cell exhaustion.
- Overexpression of ABHD17C attenuated lenvatinib's anti-proliferative and pro-apoptotic effects in vitro and reduced lenvatinib efficacy in vivo.
- Depletion of ABHD17C enhanced lenvatinib's anti-tumor activity, while lenvatinib treatment reduced ABHD17C expression in organoids.
Conclusions:
- ABHD17C promotes an immunosuppressive tumor microenvironment, thereby attenuating lenvatinib's anti-tumor effects in HCC.
- Targeting ABHD17C could be a strategy to enhance lenvatinib sensitivity.
- Modulating ABHD17C may improve therapeutic outcomes for HCC patients treated with lenvatinib.
