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Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo
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ZNF263-NuRD-mediated repression of STAT1 curtails MHC-I antigen presentation and IFN-γ efficacy in prostate cancer

Han Guan1,2,3, Likai Mao1,3, Fang Fang3

  • 1Department of Urology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China.

Proceedings of the National Academy of Sciences of the United States of America
|July 21, 2026
PubMed

Insights

ZNF263 silences major histocompatibility complex-I (MHC-I) in prostate cancer by recruiting NuRD to the STAT1 promoter. Targeting ZNF263 enhances anti-tumor immunity, improving immunotherapy outcomes.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Loss of MHC-I is a key mechanism of immune evasion in prostate cancer (PCa), leading to immunotherapy failure.
  • Understanding the regulators of MHC-I expression is crucial for developing effective PCa treatments.

Purpose of the Study:

  • To identify novel transcriptional repressors of MHC-I in PCa.
  • To elucidate the mechanisms by which ZNF263 represses MHC-I expression.
  • To evaluate ZNF263 as a therapeutic target for PCa immunotherapy.

Main Methods:

  • Investigated ZNF263's role in regulating MHC-I expression using molecular biology techniques.
  • Analyzed the impact of hypoxia on ZNF263 function, including phosphorylation and O-GlcNAcylation.
  • Utilized in silico docking to identify potential inhibitors of ZNF263-NuRD interaction.
  • Correlated ZNF263 expression with clinical parameters in PCa patients.

Main Results:

  • Identified ZNF263 as a transcriptional repressor that silences MHC-I by recruiting NuRD to the STAT1 promoter.
  • Demonstrated that hypoxia enhances ZNF263-mediated repression through phosphorylation and O-GlcNAcylation.
  • Showed that ZNF263 loss potentiates interferon-gamma (IFN-γ)-induced MHC-I expression.
  • Discovered Viroptic as a potential inhibitor disrupting ZNF263-NuRD interaction, enhancing IFN-γ antitumor immunity in vivo.
  • Found that high ZNF263 expression correlates with low MHC-I, reduced CD8+ T cells, and poor patient survival.

Conclusions:

  • ZNF263 plays a critical role in prostate cancer immune evasion by suppressing MHC-I expression.
  • Hypoxia exacerbates ZNF263-mediated immune suppression through post-translational modifications.
  • Targeting ZNF263 offers a promising strategy to overcome immunotherapy resistance in prostate cancer.
Keywords:
CD8+ T cellsIFN-γSTAT1antigen presentationprostate cancer

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