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Updated: Jul 1, 2025

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Mi-2β promotes immune evasion in melanoma by activating EZH2 methylation

Cang Li1,2, Zhengyu Wang3, Licheng Yao4

  • 1Skin Disease Research Institute, The 2nd Hospital and School of Medicine, Zhejiang University, Hangzhou, 310058, China.

Nature Communications
|March 9, 2024
PubMed

Insights

Researchers identified Mi-2β as a target to overcome resistance to cancer immunotherapy. Inhibiting Mi-2β can re-sensitize resistant melanoma tumors to immune checkpoint inhibitors, improving patient outcomes.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Immune checkpoint inhibitors (ICIs) show promise in cancer treatment, but many patients do not respond.
  • Developing strategies to convert resistant tumors to immunotherapy-sensitive is crucial for improving patient outcomes.

Purpose of the Study:

  • To identify key melanoma-intrinsic factors regulating adaptive anti-tumor immune responses.
  • To explore Mi-2β as a therapeutic target for overcoming resistance to cancer immunotherapy.

Main Methods:

  • Utilized genetically engineered mouse melanoma models.
  • Performed ATAC-seq analysis to assess gene accessibility.
  • Investigated the interaction between Mi-2β and EZH2.
  • Developed and tested an Mi-2β-targeted inhibitor (Z36-MP5).

Main Results:

  • Loss of Mi-2β rescued immune response to immunotherapy in vivo.
  • Mi-2β controls the accessibility of interferon-gamma-stimulated genes (ISGs).
  • Mi-2β promotes EZH2 methylation, inhibiting ISG transcription.
  • Z36-MP5 reactivated ISG transcription and induced ICI response in resistant melanoma models.

Conclusions:

  • Mi-2β is a critical regulator of melanoma's response to immunotherapy.
  • Targeting Mi-2β with Z36-MP5 offers a potential therapeutic strategy to convert immunotherapy-resistant melanomas into sensitive ones.

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