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Targeting WEE1 in tumor-associated dendritic cells potentiates antitumor immunity via the cGAS/STING pathway

Ian-Ian Ng1, Zhihua Zhang2, Kaimin Xiao3

  • 1State Key Laboratory of Molecular Oncology, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.

Cell Reports
|May 21, 2025
PubMed

Insights

DNA damage in tumor-associated dendritic cells (TADCs) suppresses antitumor immunity. Inhibiting WEE1 kinase in TADCs activates them, enhancing immune responses and improving tumor control, offering a new cancer immunotherapy strategy.

Area of Science:

  • Immunology
  • Cancer Biology
  • Molecular Oncology

Background:

  • DNA damage impacts cancer progression and immune function, but its effects on immune cells are understudied.
  • Tumor-associated dendritic cells (TADCs) exhibit DNA damage and upregulated WEE1 kinase, a DNA repair regulator.
  • DNA damage can paradoxically stimulate dendritic cell (DC) activation.

Purpose of the Study:

  • To investigate the role of WEE1 signaling in DNA damage repair within TADCs in the tumor microenvironment.
  • To explore the therapeutic potential of targeting WEE1 in TADCs for enhancing antitumor immunity.

Main Methods:

  • Observation of DNA damage and WEE1 expression in TADCs.
  • Assessment of TADC activation via the cGAS/STING pathway.
  • Evaluation of cytokine expression (IL-12, type I interferon) following WEE1 inhibition.
  • Analysis of WEE1 inhibition's effects on DC vaccines and immune checkpoint blockade therapy.

Main Results:

  • Significant DNA damage and WEE1 upregulation were observed in TADCs.
  • WEE1 inhibition in TADCs led to activation via the cGAS/STING pathway.
  • Inhibition increased IL-12 and type I interferon, boosting antitumor immune response and tumor control.
  • WEE1 inhibition enhanced DC vaccine efficacy and synergized with immune checkpoint blockade.

Conclusions:

  • WEE1 signaling in TADCs plays a critical role in DNA damage repair, suppressing antitumor immunity within the tumor microenvironment.
  • Targeting WEE1 in DCs is a promising strategy to enhance T cell activation and improve cancer immunotherapy outcomes.
Keywords:
CP: CancerCP: ImmunologyDNA damageWEE1antigen presentationcancer immunotherapydendritic cells

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