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Updated: May 9, 2025

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Permanent Efferocytosis Prevention by Terminating MerTK Recycle on Tumor-Associated Macrophages for Cancer

Pei Huang1, Yiwen Liu2,3, Caiyan Zhao2,3

  • 1Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore.

Journal of the American Chemical Society
|April 28, 2025
PubMed

Insights

Blocking phosphatidylserine (PtdSer) and MER proto-oncogene tyrosine kinase (MerTK) with antibodies offers temporary tumor immunosuppression relief. Gene editing to permanently knock out MerTK provides durable efferocytosis prevention and sustained tumor suppression.

Area of Science:

  • Immunology
  • Oncology
  • Gene Editing

Background:

  • Efferocytosis of apoptotic tumor cells by tumor-associated macrophages via the phosphatidylserine (PtdSer)/MER proto-oncogene tyrosine kinase (MerTK) axis promotes tumor immunosuppression.
  • Antibody blockade of PtdSer-MerTK interaction is a strategy to reverse immunosuppression and enhance antitumor immunity.

Purpose of the Study:

  • To investigate the durability of antibody-mediated efferocytosis prevention and its impact on tumor growth inhibition.
  • To develop a more effective and sustained strategy for modulating MerTK activity in cancer immunotherapy.

Main Methods:

  • Utilized PtdSer and MerTK antibodies to assess efferocytosis prevention and tumor growth inhibition.
  • Investigated mechanisms of transient therapeutic effects, including antibody degradation and receptor recycling.
  • Developed and employed a CRISPR/Cas9 gene editing system (Cas9 mRNA and MerTK sgRNA) for permanent MerTK knockout.
  • Evaluated the combination of gene editing, anti-PtdSer antibody, and X-ray irradiation in B16 melanoma models.

Main Results:

  • Antibody blockade of PtdSer-MerTK interaction provided only transient efferocytosis prevention and limited tumor growth inhibition.
  • Mechanistic studies revealed antibody degradation and MerTK receptor recycling as limitations to sustained blockade.
  • CRISPR/Cas9-mediated permanent MerTK knockout achieved durable efferocytosis prevention.
  • The gene editing strategy enhanced X-ray irradiation-induced immunogenic cell death, leading to persistent in situ vaccination immune responses and sustained tumor suppression.

Conclusions:

  • Permanent MerTK knockout via CRISPR/Cas9 offers a durable strategy for overcoming MerTK-dependent cancer immune evasion.
  • This gene-editing approach combined with immunotherapy can generate adaptive antitumor immune responses for sustained cancer treatment.
  • The findings provide a novel gene-editing-mediated platform for long-term modulation of MerTK homeostasis in cancer immunotherapy.

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