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Updated: Jun 4, 2025

An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
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Sorafenib Promotes Treg Cell Differentiation To Compromise Its Efficacy via VEGFR/AKT/Foxo1 Signaling in

Yingying Shen1, Hanliang Wang1, Zeyu Ma2

  • 1Department of Medical Oncology, Zhejiang Key Laboratory of Multi-omics Precision Diagnosis and Treatment of Liver Diseases, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, Zhejiang, China.

Cellular and Molecular Gastroenterology and Hepatology
|January 1, 2025
PubMed
Abstract

Insights

Sora treatment for liver cancer (HCC) promotes regulatory T (Treg) cell differentiation, suppressing the immune response and causing resistance. Inactivating Treg cells with anti-CD25 or a Foxo1 inhibitor alongside Sora enhances treatment efficacy.

Area of Science:

  • Immunology
  • Oncology
  • Pharmacology

Background:

  • Sora is a first-line treatment for advanced hepatocellular carcinoma (HCC).
  • Acquired resistance to Sora significantly limits its therapeutic effectiveness.
  • Mechanisms driving Sora resistance in HCC are not fully understood.

Purpose of the Study:

  • To elucidate the mechanism by which Sora induces resistance in HCC.
  • To investigate the role of regulatory T (Treg) cells in Sora resistance.
  • To explore strategies for overcoming Sora resistance in HCC.

Main Methods:

  • Analysis of immune cells in HCC tumor microenvironment (TME) using flow cytometry.
  • Evaluation of Treg cell differentiation via RT-PCR and ELISA.
  • Assessment of protein expression and signaling pathways (VEGFR/AKT/Foxo1).
  • Treatment of HCC tumor models with Sora, anti-CD25 antibody, or Foxo1 inhibitor AS1842856.

Main Results:

  • Sora treatment promotes Treg cell differentiation and increases their immunosuppressive activity in HCC.
  • Sora-induced Treg cell differentiation is dependent on the VEGFR/AKT/Foxo1 pathway.
  • Combined treatment with Sora and Treg inactivation (anti-CD25 or AS1842856) demonstrated enhanced efficacy in HCC models.

Conclusions:

  • Sora induces Treg cell differentiation by inhibiting VEGFR/AKT signaling and activating Foxo1, leading to immune suppression and resistance.
  • Inactivating Treg cells represents a potential strategy to overcome Sora resistance and improve HCC treatment outcomes.
Keywords:
Foxo1Hepatocellular CarcinomaImmunosuppressionSora ResistanceTreg Cells

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