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DTX3 promotes anti-tumor immunity by inducing PD-L1 ubiquitination and is suppressed by p65/miR-222 in bladder cancer

Yu Cheng1, Ya Chen2, JiaYu Wang3,4

  • 1Department of Pathology, Cancer Research Laboratory, Chengde Medical University, Chengde, China.

Oncogene
|July 23, 2026
PubMed

Insights

Deltex E3 ubiquitin ligase 3 (DTX3) enhances anti-tumor immunity by degrading PD-L1, improving immunotherapy for bladder cancer. DTX3

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Limited efficacy of PD-L1/PD-1 immunotherapy in bladder cancer (BC) presents a significant clinical challenge.
  • Identifying novel regulators of PD-L1 expression is crucial for enhancing anti-tumor immunity.

Purpose of the Study:

  • To identify and characterize novel regulators of PD-L1 expression in bladder cancer.
  • To investigate the therapeutic potential of targeting DTX3 to improve anti-PD-1 immunotherapy efficacy.

Main Methods:

  • Whole-exome sequencing (WES) and functional screening to identify DTX3 as a PD-L1 regulator.
  • In vitro and in vivo studies using syngeneic mouse models to assess anti-tumor effects.
  • Mechanistic studies involving protein interaction, ubiquitination assays, and analysis of the p65/miR-222 axis.

Main Results:

  • DTX3 was identified as a negative regulator of PD-L1 expression.
  • DTX3 overexpression enhanced T cell activity, increased IFN-γ secretion, and improved anti-PD-1 antibody efficacy.
  • DTX3 promotes PD-L1 polyubiquitination and proteasomal degradation.
  • The p65/miR-222 axis suppresses DTX3, leading to increased PD-L1 levels.

Conclusions:

  • DTX3 enhances anti-tumor immunity by promoting PD-L1 ubiquitination and degradation.
  • DTX3 is a potential therapeutic target to overcome resistance to PD-1/PD-L1 immunotherapy in bladder cancer.
  • Modulating the p65/miR-222/DTX3 pathway could improve treatment outcomes.

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