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

Shiqun Wang, Wenyan Yang, Ti Peng, Chunxiao Zhu, Jinyun Dong, Yichao Wang, Hu Yuan, Qingyan Sun, Xin Luan, Xiaoqing Guan (), Weidong Zhang () and Jiang-Jiang Qin ()
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Shiqun Wang: Chinese Academy of Sciences, Center for Innovative Drug Research, Hangzhou Institute of Medicine (HIM)
Wenyan Yang: Chinese Academy of Sciences, Center for Innovative Drug Research, Hangzhou Institute of Medicine (HIM)
Ti Peng: Chinese Academy of Sciences, Center for Innovative Drug Research, Hangzhou Institute of Medicine (HIM)
Chunxiao Zhu: Chinese Academy of Sciences, Center for Innovative Drug Research, Hangzhou Institute of Medicine (HIM)
Jinyun Dong: Chinese Academy of Sciences, Center for Innovative Drug Research, Hangzhou Institute of Medicine (HIM)
Yichao Wang: Chinese Academy of Sciences, Center for Innovative Drug Research, Hangzhou Institute of Medicine (HIM)
Hu Yuan: China State Institute of Pharmaceutical Industry, State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry
Qingyan Sun: China State Institute of Pharmaceutical Industry, State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry
Xin Luan: Shanghai University of Traditional Chinese Medicine, Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research
Xiaoqing Guan: Zhejiang Cancer Hospital, Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology
Weidong Zhang: China State Institute of Pharmaceutical Industry, State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry
Jiang-Jiang Qin: Chinese Academy of Sciences, Center for Innovative Drug Research, Hangzhou Institute of Medicine (HIM)

Nature Communications, 2025, vol. 16, issue 1, 1-25

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-65762-4

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