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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
12:42

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Targeting MORC2 activates transposable element-mediated viral mimicry and potentiates immune checkpoint blockade in

Fang-Lin Zhang1,2, Shao-Ying Yang3,4, Yin-Ling Zhang3,4

  • 1Department of Oncology, Cancer Institute, Shanghai Medical College, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China. zhangfanglin555@sina.com.

Molecular Cancer
|May 29, 2026
PubMed

Insights

MORC2, an epigenetic regulator, suppresses anti-tumor immunity in triple-negative breast cancer (TNBC). Targeting MORC2 with antisense oligonucleotides (ASOs) combined with anti-PD-1 therapy shows promise for overcoming immune checkpoint blockade resistance in TNBC.

Area of Science:

  • Immunology
  • Epigenetics
  • Oncology

Background:

  • Immune checkpoint blockade (ICB) efficacy is limited in triple-negative breast cancer (TNBC).
  • Understanding immune evasion mechanisms and identifying novel therapeutic targets in TNBC is crucial.
  • MORC2 (MORC family CW-type zinc finger 2) is an ATP-dependent chromatin remodeler implicated in epigenetic regulation.

Purpose of the Study:

  • To identify MORC2 as a key epigenetic suppressor of antitumor immunity in TNBC.
  • To elucidate the mechanism by which MORC2 contributes to immune evasion.
  • To evaluate the therapeutic potential of targeting MORC2 in TNBC.

Main Methods:

  • Genetic ablation of MORC2 in mouse TNBC models.
  • Assessing tumor growth in immunocompetent and immunodeficient mice.
  • Investigating MORC2's interaction with SETDB1 and its role in H3K9me3 deposition at transposable elements.
  • Therapeutic targeting of MORC2 using antisense oligonucleotides (ASOs) in combination with anti-PD-1 therapy.
  • Analyzing MORC2 expression and CD8+ T cell infiltration in human TNBC samples.

Main Results:

  • MORC2 is upregulated in TNBC and correlates with an immunosuppressive tumor microenvironment and poor ICB response.
  • MORC2 ablation inhibited tumor growth in immunocompetent mice, enhancing CD8+ T cell cytotoxicity and M1 macrophage polarization.
  • MORC2, with SETDB1, silences transposable elements via H3K9me3, suppressing viral mimicry and interferon responses.
  • SETDB1-mediated MORC2 methylation enhances its stability, creating a positive feedback loop.
  • Therapeutic targeting of MORC2 with ASOs synergized with anti-PD-1 therapy to suppress tumor growth.
  • Clinical data showed an inverse correlation between MORC2 expression and CD8+ T cell infiltration/activation in human TNBC.

Conclusions:

  • MORC2 acts as a novel epigenetic immune checkpoint in TNBC.
  • MORC2 promotes immune evasion by epigenetically silencing antiviral response pathways.
  • Targeting MORC2 represents a promising therapeutic strategy to enhance ICB efficacy in TNBC.
Keywords:
Chromatin remodelingImmunotherapyTranscriptional repressionTriple-negative breast cancerTumor immune microenvironment

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