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Updated: Jan 10, 2026

Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer
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Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer

Published on: January 17, 2025

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IFN-γ-driven UBE2D3 upregulation impairs antigen presentation pathways and anti-tumor immunity in pancreatic cancer

Shiqun Wang1,2,3, Wenyan Yang1,4, Ti Peng1

  • 1Center for Innovative Drug Research, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China.

Nature Communications
|November 28, 2025
PubMed

Insights

Overexpression of Ubiquitin-Conjugating Enzyme E2 D3 (UBE2D3) in pancreatic cancer helps tumors evade immune detection. Inhibiting UBE2D3 restores immune surveillance and enhances T-cell therapy effectiveness against pancreatic ductal adenocarcinoma.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Ubiquitin-conjugating enzymes are crucial for cellular processes, but their role in cancer, particularly pancreatic cancer, is not fully understood.
  • Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with limited treatment options, necessitating novel therapeutic targets.

Purpose of the Study:

  • To investigate the role of Ubiquitin-Conjugating Enzyme E2 D3 (UBE2D3) in pancreatic cancer.
  • To elucidate the mechanism by which UBE2D3 influences tumor immunity and to explore its therapeutic potential.

Main Methods:

  • Genetic and molecular analyses were performed on pancreatic cancer cells and patient samples.
  • Investigated the interaction between UBE2D3, KLHL13, and TAP2.
  • Assessed the impact of UBE2D3 inhibition on antigen presentation and CD8+ T-cell responses in preclinical models.
  • Evaluated combination therapy with UBE2D3 inhibitors and TCR-T-cell therapy.

Main Results:

  • UBE2D3 is significantly overexpressed in pancreatic ductal cells, including early and advanced PDAC, driven by interferon-gamma (IFN-γ).
  • UBE2D3 overexpression blocks antigen transporter TAP2 via polyubiquitination, impairing antigen presentation and immune evasion.
  • Inhibition of UBE2D3 enhances antigen presentation and restores CD8+ T-cell-mediated tumor surveillance in pancreatic cancer models.
  • Combined UBE2D3 inhibition and KRAS-specific TCR-T-cell therapy demonstrated synergistic antitumor effects.

Conclusions:

  • UBE2D3 acts as a key mediator of immune evasion in pancreatic cancer by suppressing antigen presentation.
  • Targeting UBE2D3 represents a promising therapeutic strategy to enhance antitumor immunity and improve the efficacy of immunotherapy in PDAC.

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