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<p>Although ubiquitin-conjugating enzymes are critical regulators of cellular function and fate, their roles in tumorigenesis remain incompletely defined. Here, we provide genetic and molecular evidence that the Ubiquitin-Conjugating Enzyme E2 D3 (UBE2D3) is specifically overexpressed in cancerous pancreatic ductal cells, including early-stage pancreatic intraepithelial neoplasia and advanced pancreatic ductal adenocarcinoma (PDAC). This overexpression is independent of oncogenic KRAS status and is driven by the inflammatory tumor microenvironment, particularly interferon-γ (IFN-γ). Mechanistically, UBE2D3 binds the ubiquitin ligase Kelch Like Family Member 13 (KLHL13) to mediate K63-linked polyubiquitination at lysine 245 of transporter 2 (TAP2), resulting in steric hindrance that blocks the transporter. Genetic or pharmacologic inhibition of UBE2D3 enhances antigen presentation in cancer cells and restores CD8<sup>+</sup> T-cell-mediated tumor surveillance in pancreatic cancer models in male mice. Furthermore, combining an UBE2D3 small-molecule inhibitor with KRAS<sup>G12D</sup>-specific TCR-T-cell therapy yields synergistic antitumor effects. Our findings reveal a negative feedback mechanism in which cancer cells, “camouflaging” themselves, evade IFN-γ-induced antigen presentation via UBE2D3 upregulation, highlighting a potential therapeutic target for enhancing antitumor immunity.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月28日

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  • Shiqun Wang,
  • Wenyan Yang,
  • Ti Peng,
  • Chunxiao Zhu,
  • Jinyun Dong,
  • Yichao Wang,
  • Hu Yuan,
  • Qingyan Sun,
  • Xin Luan,
  • Xiaoqing Guan,
  • Weidong Zhang,
  • Jiang-Jiang Qin

摘要

Although ubiquitin-conjugating enzymes are critical regulators of cellular function and fate, their roles in tumorigenesis remain incompletely defined. Here, we provide genetic and molecular evidence that the Ubiquitin-Conjugating Enzyme E2 D3 (UBE2D3) is specifically overexpressed in cancerous pancreatic ductal cells, including early-stage pancreatic intraepithelial neoplasia and advanced pancreatic ductal adenocarcinoma (PDAC). This overexpression is independent of oncogenic KRAS status and is driven by the inflammatory tumor microenvironment, particularly interferon-γ (IFN-γ). Mechanistically, UBE2D3 binds the ubiquitin ligase Kelch Like Family Member 13 (KLHL13) to mediate K63-linked polyubiquitination at lysine 245 of transporter 2 (TAP2), resulting in steric hindrance that blocks the transporter. Genetic or pharmacologic inhibition of UBE2D3 enhances antigen presentation in cancer cells and restores CD8+ T-cell-mediated tumor surveillance in pancreatic cancer models in male mice. Furthermore, combining an UBE2D3 small-molecule inhibitor with KRASG12D-specific TCR-T-cell therapy yields synergistic antitumor effects. Our findings reveal a negative feedback mechanism in which cancer cells, “camouflaging” themselves, evade IFN-γ-induced antigen presentation via UBE2D3 upregulation, highlighting a potential therapeutic target for enhancing antitumor immunity.