VDAC2 loss elicits tumour destruction and inflammation for cancer therapy

Sujing Yuan, Renqiang Sun, Hao Shi, Nicole M. Chapman, Haoran Hu, Cliff Guy, Sherri Rankin, Anil Kc, Gustavo Palacios, Xiaoxi Meng, Xiang Sun, Peipei Zhou, Xiaoyang Yang, Stephen Gottschalk and Hongbo Chi ()
Additional contact information
Sujing Yuan: St. Jude Children’s Research Hospital
Renqiang Sun: St. Jude Children’s Research Hospital
Hao Shi: St. Jude Children’s Research Hospital
Nicole M. Chapman: St. Jude Children’s Research Hospital
Haoran Hu: St. Jude Children’s Research Hospital
Cliff Guy: St. Jude Children’s Research Hospital
Sherri Rankin: St. Jude Children’s Research Hospital
Anil Kc: St. Jude Children’s Research Hospital
Gustavo Palacios: St. Jude Children’s Research Hospital
Xiaoxi Meng: St. Jude Children’s Research Hospital
Xiang Sun: St. Jude Children’s Research Hospital
Peipei Zhou: St. Jude Children’s Research Hospital
Xiaoyang Yang: St. Jude Children’s Research Hospital
Stephen Gottschalk: St. Jude Children’s Research Hospital
Hongbo Chi: St. Jude Children’s Research Hospital

Nature, 2025, vol. 640, issue 8060, 1062-1071

Abstract: Abstract Tumour cells often evade immune pressure exerted by CD8+ T cells or immunotherapies through mechanisms that are largely unclear1,2. Here, using complementary in vivo and in vitro CRISPR–Cas9 genetic screens to target metabolic factors, we established voltage-dependent anion channel 2 (VDAC2) 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 CD8+ T 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.

Date: 2025
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DOI: 10.1038/s41586-025-08732-6

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