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Updated: Jun 30, 2025

Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology
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Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology

Published on: May 2, 2025

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DDX3 regulates cancer immune surveillance via 3' UTR-mediated cell-surface expression of PD-L1

Hung-Hsi Chen1, Hsin-I Yu1, Jason Jie-Sheng Chang1

  • 1Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.

Cell Reports
|March 15, 2024
PubMed

Insights

Inhibition of RNA helicase DDX3 enhances anti-cancer immunity by reducing PD-L1 on tumor cells. This DDX3-AP2 pathway controls PD-L1 cell surface expression, offering a novel immunotherapy target.

Area of Science:

  • Immunology
  • Molecular Biology
  • Oncology

Background:

  • Programmed death-1 (PD-1)/PD ligand-1 (PD-L1) pathway is crucial for cancer immune evasion.
  • Targeting PD-1/PD-L1 is an established anti-cancer immunotherapy strategy.

Purpose of the Study:

  • To investigate the role of RNA helicase DDX3 in regulating PD-L1 expression and immune cell infiltration in oral squamous cell carcinoma.
  • To elucidate the mechanism by which DDX3 influences PD-L1 cell surface trafficking.

Main Methods:

  • Utilized syngeneic oral squamous cell carcinoma tumor models.
  • Performed DDX3 knockdown and assessed CD8+ T cell infiltration.
  • Investigated the effect of DDX3 on interferon-γ-induced PD-L1 expression and cell-surface levels.
  • Examined the interaction of DDX3 with the 3' UTR of PD-L1 mRNA and the AP2 complex.
  • Assessed the impact of disrupting the DDX3-AP2 interaction on PD-L1 trafficking.

Main Results:

  • DDX3 inhibition increased CD8+ T cell infiltration in tumors.
  • DDX3 knockdown reduced interferon-γ-induced PD-L1 expression and cell-surface levels.
  • DDX3 recruits the AP2 complex to the PD-L1 mRNA 3' UTR, promoting cell surface expression.
  • Disruption of the DDX3-AP2 interaction decreased surface PD-L1 levels.

Conclusions:

  • The DDX3-AP2 pathway is essential for routing PD-L1 to the cell surface in oral squamous cell carcinoma.
  • Targeting DDX3 to modulate immune checkpoint protein trafficking presents a potential cancer immunotherapy strategy.
Keywords:
3’ UTR-mediated protein-protein interactionCP: CancerCP: ImmunologyYXXØsorting motif

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