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Updated: Oct 12, 2025

In Vivo Immunogenicity Screening of Tumor-Derived Extracellular Vesicles by Flow Cytometry of Splenic T Cells
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WEE1 inhibition induces anti-tumor immunity by activating ERV and the dsRNA pathway

Ensong Guo1,2,3, Rourou Xiao1,2,3, Yifan Wu1,2,3,4

  • 1National Clinical Research Center for Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

The Journal of Experimental Medicine
|November 26, 2021
PubMed

Insights

Targeting WEE1 kinase activates the body's natural antiviral defenses, making tumors more responsive to immune checkpoint blockade (ICB) therapy, even in difficult-to-treat cancers.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Immune checkpoint blockade (ICB) shows promise but benefits limited patients.
  • Targeted therapies are explored to enhance ICB efficacy and overcome resistance.
  • WEE1 kinase is a potential target for modulating anti-tumor immunity.

Purpose of the Study:

  • To investigate if WEE1 inhibition can enhance anti-tumor immunity and ICB response.
  • To elucidate the mechanisms by which WEE1 inhibition impacts the tumor microenvironment.
  • To identify biomarkers for predicting response to combination therapy.

Main Methods:

  • Inhibition of WEE1 kinase in various cancer models.
  • Analysis of immune signaling pathways, including double-stranded RNA (dsRNA) response.
  • Assessment of endogenous retroviral elements (ERVs) expression and epigenetic modifications.
  • Evaluation of T cell infiltration and PD-L1 expression.
  • Combination therapy studies with WEE1 inhibitors and PD-L1 blockade.

Main Results:

  • WEE1 inhibition up-regulates immune signaling via the dsRNA viral defense pathway.
  • This effect occurs even in cGAS/STING-deficient tumors, enhancing ICB responsiveness.
  • WEE1 inhibition increases ERVs expression by relieving SETDB1/H3K9me3 repression.
  • ERVs trigger interferon response, increasing CD8+ T cell recruitment and PD-L1 levels.
  • Combined WEE1 inhibition and PD-L1 blockade resulted in significant tumor regression dependent on CD8+ T cells.

Conclusions:

  • WEE1 inhibition stimulates anti-tumor immunity and enhances sensitivity to ICB.
  • A WEE1 inhibition-induced viral defense signature may serve as a predictive biomarker.
  • Combination therapy with WEE1 inhibitors and ICB is a promising strategy for cancer treatment.

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