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<p>The limited efficacy of programmed death ligand-1 (PD-L1)/programmed death 1 (PD-1) immunotherapy remains a major challenge in bladder cancer (BC). Here, we identified Deltex E3 ubiquitin ligase 3 (DTX3) as a negative regulator of PD-L1 expression through whole-exome sequencing (WES) and functional screening. DTX3 overexpression inhibited CD3⁺CD8⁺ T cell apoptosis via the PD-1/PD-L1 axis, increased IFN-γ secretion, and enhanced the anti-tumor effect of anti-PD-1 monoclonal antibody (mAb). Mechanistically, DTX3 interacted with PD-L1 and promoted its polyubiquitination and proteasomal degradation. DTX3 overexpression combined with anti-PD-1 mAb produced significantly stronger anti-tumor effects than either monotherapy in syngeneic mouse models. Furthermore, DTX3 was identified as a direct target of miR-222, which is transcriptionally downregulated by p65. NF-κB activation decreased DTX3 expression and increased PD-L1 levels; combining a p65 inhibitor with DTX3 overexpression significantly reduced tumor growth in vivo. These findings demonstrate that DTX3 enhances anti-tumor immunity by inducing PD-L1 ubiquitination and is suppressed by the p65/miR-222 axis, highlighting DTX3 as a potential therapeutic target to improve immunotherapy efficacy in BC.</p>

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

  • 期刊论文

  • 发表日期：

    2026年7月24日

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  • Yu Cheng,
  • Ya Chen,
  • JiaYu Wang,
  • Zhun Shu,
  • YuanZhong Yang,
  • YuanZhong Wu,
  • ZhiYong Li,
  • YiJun Zhang

摘要

The limited efficacy of programmed death ligand-1 (PD-L1)/programmed death 1 (PD-1) immunotherapy remains a major challenge in bladder cancer (BC). Here, we identified Deltex E3 ubiquitin ligase 3 (DTX3) as a negative regulator of PD-L1 expression through whole-exome sequencing (WES) and functional screening. DTX3 overexpression inhibited CD3⁺CD8⁺ T cell apoptosis via the PD-1/PD-L1 axis, increased IFN-γ secretion, and enhanced the anti-tumor effect of anti-PD-1 monoclonal antibody (mAb). Mechanistically, DTX3 interacted with PD-L1 and promoted its polyubiquitination and proteasomal degradation. DTX3 overexpression combined with anti-PD-1 mAb produced significantly stronger anti-tumor effects than either monotherapy in syngeneic mouse models. Furthermore, DTX3 was identified as a direct target of miR-222, which is transcriptionally downregulated by p65. NF-κB activation decreased DTX3 expression and increased PD-L1 levels; combining a p65 inhibitor with DTX3 overexpression significantly reduced tumor growth in vivo. These findings demonstrate that DTX3 enhances anti-tumor immunity by inducing PD-L1 ubiquitination and is suppressed by the p65/miR-222 axis, highlighting DTX3 as a potential therapeutic target to improve immunotherapy efficacy in BC.