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Updated: Nov 8, 2025

Co-immunoprecipitation Assay for Studying Functional Interactions Between Receptors and Enzymes
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EZH2 inhibition activates a dsRNA-STING-interferon stress axis that potentiates response to PD-1 checkpoint blockade

Katherine L Morel1, Anjali V Sheahan1, Deborah L Burkhart1

  • 1Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.

Nature Cancer
|April 26, 2021
PubMed

Insights

Inhibiting enhancer of zeste homolog-2 (EZH2) in prostate cancer models activates an interferon-stimulated gene (ISG) response. This approach enhances antitumor immunity and improves responsiveness to checkpoint inhibitor (CPI) therapy.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Prostate cancer is often immunologically 'cold,' with limited response to checkpoint inhibitor (CPI) therapy.
  • Interferon-stimulated genes (ISGs) are linked to favorable CPI responses in various cancers.
  • Enhancer of zeste homolog-2 (EZH2) is overexpressed in prostate cancer and suppresses ISGs.

Purpose of the Study:

  • To investigate the role of EZH2 in regulating antitumor immunity in prostate cancer.
  • To determine if EZH2 inhibition can overcome resistance to CPI therapy.

Main Methods:

  • Utilized prostate cancer models to study the effects of EZH2 inhibition.
  • Analyzed the activation of the double-stranded RNA-STING-ISG pathway.
  • Assessed changes in immune cell infiltration and gene expression.

Main Results:

  • EZH2 inhibition activated the STING-ISG pathway, upregulating antigen presentation and interferon response genes.
  • Programmed cell death protein 1 (PD-L1) expression was increased, dependent on STING activation.
  • Increased CD8+ T cell trafficking and M1 tumor-associated macrophages were observed.
  • Resistance to PD-1 CPI was reversed.

Conclusions:

  • EZH2 acts as a significant inhibitor of antitumor immunity and CPI responsiveness.
  • EZH2 inhibition represents a potential therapeutic strategy to enhance prostate cancer response to PD-1 CPI.

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