VDAC2 loss elicits tumour destruction and inflammation for cancer therapy

• 成果类型: Article
• 署名作者: Yuan, Sujing; Sun, Renqiang; Shi, Hao; Chapman, Nicole M.; Hu, Haoran; Guy, Cliff; Rankin, Sherri; Kc, Anil; Palacios, Gustavo; Meng, Xiaoxi; Sun, Xiang; Zhou, Peipei; Yang, Xiaoyang; Gottschalk, Stephen; Chi, Hongbo
• 署名单位: St Jude Children's Research Hospital; St Jude Children's Research Hospital; St Jude Children's Research Hospital
• 刊物名称: Nature
• ISSN/ISSBN: 0028-0991
• DOI: 10.1038/s41586-025-08732-6
• 发表日期: 2025-04-24
• 关键词: t-cells; acquired-resistance; clinical-response; landscape; immunity; target; identification; requires; screens; subsets

摘要

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-gamma (IFN gamma)-mediated tumour destruction and inflammatory reprogramming of the tumour microenvironment. Targeting VDAC2 in tumour cells enabled IFN gamma-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, IFN gamma stimulation increased BIM, BID and BAK expression, with VDAC2 deficiency eliciting uncontrolled IFN gamma-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 IFN gamma-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.