NatureMar 20, 2025

Losing VDAC2 triggers tumor breakdown and inflammation for cancer treatment

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jan 19, 2026

Abstract

Targeting voltage-dependent anion channel 2 () in tumour cells could improve anti-tumour effects and immunotherapeutic responses.

VDAC2 is identified as an immune signal-dependent checkpoint that limits the effectiveness of interferon-γ (IFNγ) in destroying tumours.
Inhibition of VDAC2 allows for increased IFNγ-induced cell death and activation of the .
Loss of VDAC2 leads to heightened activation of BAK, resulting in mitochondrial damage and the release of mitochondrial DNA into the cytosol.
Mitochondrial DNA release triggers a strong immune response via cGAS-STING signalling and type I interferon activation.
Co-deleting STING signalling components reduces the therapeutic benefits of targeting VDAC2, indicating its role in linking adaptive and innate immune responses.

Simplified

Tumour cells often evade immune pressure exerted by CD8T cells or immunotherapies through mechanisms that are largely unclear. Here, using complementary in vivo and in vitro CRISPR-Cas9 genetic screens to target metabolic factors, we established voltage-dependent anion channel 2 () as an immune signal-dependent checkpoint that curtails interferon-γ (IFNγ)-mediated tumour destruction and inflammatory reprogramming of the tumour microenvironment. Targeting VDAC2 in tumour cells enabled IFNγ-induced cell death and cGAS-STING activation, and markedly improved anti-tumour effects and immunotherapeutic responses. Using a genome-scale genetic interaction screen, we identified BAK as the mediator of VDAC2-deficiency-induced effects. Mechanistically, IFNγ stimulation increased BIM, BID and BAK expression, with VDAC2 deficiency eliciting uncontrolled IFNγ-induced BAK activation and mitochondrial damage. Consequently, mitochondrial DNA was aberrantly released into the cytosol and triggered robust activation of cGAS-STING signalling and type I IFN response. Importantly, co-deletion of STING signalling components dampened the therapeutic effects of VDAC2 depletion in tumour cells, suggesting that targeting VDAC2 integrates CD8T cell- and IFNγ-mediated adaptive immunity with a tumour-intrinsic innate immune-like response. Together, our findings reveal VDAC2 as a dual-action target to overcome tumour immune evasion and establish the importance of coordinately destructing and inflaming tumours to enable efficacious cancer immunotherapy. + 1,2 +

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Competing interests

Competing interests: S.G. is a member of the Scientific Advisory Board of Be Biopharma and CARGO and the Data and Safety Monitoring Board (DSMB) of Immatics, and is a co-inventor on patents/patent applications in the fields of immunotherapy and gene therapy. H.C. consults for Kumquat Biosciences and TCura Bioscience, and is a co-inventor on patents/patent applications in the field of immunotherapy. The remaining authors declare no competing interests.

PubMed

Losing VDAC2 triggers tumor breakdown and inflammation for cancer treatment

Abstract

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Funding

Competing interests

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