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0 reviewsTumour cells often evade immune pressure exerted by CD8+ T cells or immunotherapies Open accessthrough mechanisms that are largely unclear1,2. Here, using complementary in vivo Check for updatesand 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 infammatory reprogramming of the tumour microenvironment. Targeting VDAC2 in tumour cells enabled IFNγ-induced cell death and cGAS–STING activation, and markedly improved anti-tumour efects and immunotherapeutic responses. Using a genome-scale genetic interaction screen, we identifed BAK as the mediator of VDAC2-defciency-induced efects. Mechanistically, IFNγ stimulation increased BIM, BID and BAK expression, with VDAC2 defciency 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 efects 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 fndings reveal VDAC2 as a dual-action target to overcome tumour immune evasion and establish the importance of coordinately destructing and infaming tumours to enable efcacious cancer immunotherapy.