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VDAC2 brake release: unleashing inflammation via IFNγ

Swapneel J Patel1, Zhijian J Chen2

  • 1Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Trends in Pharmacological Sciences
|July 30, 2025
PubMed

Insights

Targeting VDAC2 in tumors enhances cancer sensitivity to interferon-gamma (IFNγ) therapy. This occurs via mitochondrial DNA release and activation of the cGAS-STING pathway, suggesting VDAC2 inhibition as a novel therapeutic strategy.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Identifying therapeutic vulnerabilities is crucial for advancing cancer treatment.
  • The CRISPR/Cas9 screening platform enables large-scale genetic analysis in cancer research.
  • Interferon-gamma (IFNγ) is a key cytokine in immune responses against tumors.

Purpose of the Study:

  • To investigate the role of VDAC2 in cancer therapy sensitivity.
  • To elucidate the molecular mechanisms by which VDAC2 affects tumor response to IFNγ.
  • To explore VDAC2 inhibition as a potential strategy to enhance antitumor therapies.

Main Methods:

  • Utilized CRISPR/Cas9 screening to identify genetic vulnerabilities in cancer.
  • Investigated the effect of VDAC2 deletion on tumor sensitivity to IFNγ.
  • Analyzed the release of mitochondrial DNA (mtDNA) and its role in immune activation.
  • Examined the involvement of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway.

Main Results:

  • VDAC2 deletion in tumors significantly increased sensitivity to IFNγ.
  • Tumor VDAC2 deletion led to the release of mitochondrial DNA (mtDNA).
  • Released mtDNA activated the cGAS-STING pathway, contributing to IFNγ sensitivity.

Conclusions:

  • VDAC2 plays a critical role in regulating tumor response to IFNγ.
  • VDAC2 inhibition represents a promising approach to potentiate IFNγ-based cancer immunotherapies.
  • Targeting VDAC2 could overcome resistance mechanisms and improve treatment outcomes.
Keywords:
STINGVDACcGAScancerinflammation

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