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Updated: Jul 23, 2025

Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
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Loss of PHF8 induces a viral mimicry response by activating endogenous retrotransposons

Yanan Liu1, Longmiao Hu1, Zhengzhen Wu1

  • 1Shanghai Key Laboratory of Regulatory Biology and School of Life Sciences, East China Normal University, Shanghai, China.

Nature Communications
|July 15, 2023
PubMed

Insights

PHD finger protein 8 (PHF8) is a key driver of immune escape in colorectal cancer. Targeting PHF8 triggers a viral mimicry response, enhancing anti-tumor immunity and improving response to immune checkpoint blockade therapy.

Area of Science:

  • Epigenetics
  • Cancer Immunology
  • Molecular Biology

Background:

  • Immunotherapy, including immune checkpoint blockade (ICB), is a vital treatment for colorectal cancer.
  • Novel therapeutic targets are needed to enhance anti-tumor immunity and overcome resistance to ICB.
  • PHD finger protein 8 (PHF8) is a histone demethylase involved in epigenetic regulation.

Purpose of the Study:

  • To investigate the role of PHF8 in colorectal cancer immune escape.
  • To determine if targeting PHF8 can enhance anti-tumor immunity and ICB efficacy.
  • To elucidate the mechanism by which PHF8 influences the tumor microenvironment.

Main Methods:

  • Utilized mouse models of colorectal cancer with PHF8 ablation.
  • Assessed tumor growth, anti-tumor immune memory, and response to ICB therapy.
  • Investigated PHF8's impact on viral mimicry, nucleic acid sensing pathways, and epigenetic modifications (H3K9me3, SETDB1).
  • Analyzed PHF8 expression in human colorectal adenocarcinoma tissues.

Main Results:

  • PHF8 ablation significantly inhibited tumor growth and activated anti-tumor immune memory in mouse models.
  • PHF8 deletion induced a viral mimicry response, increasing sensitivity to ICB therapy.
  • PHF8 inhibition led to H3K9me3-dependent retrotransposon activation via SETDB1 degradation.
  • PHF8 expression inversely correlated with immune signatures and antiviral responses in human colorectal cancer.

Conclusions:

  • PHF8 acts as an epigenetic checkpoint mediating immune escape in colorectal cancer.
  • Targeting PHF8 represents a promising strategy to induce viral mimicry, boost intrinsic anti-tumor immunity, and overcome ICB resistance.

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