VDAC2缺失引发肿瘤破坏和炎症，可用于癌症治疗，这一成果由圣犹达儿童研究医院Chi, Hongbo研究组经过不懈努力而取得。2025年3月19日出版的《自然》杂志发表了这一最新研究成果。

在体内和体外CRISPR-Cas9基因筛选的基础上，课题组建立了电压依赖性阴离子通道2 （VDAC2）作为免疫信号依赖性检查点，可以抑制干扰素-γ (IFNγ)介导的肿瘤破坏和肿瘤微环境的炎症重编程。在肿瘤细胞中靶向VDAC2使IFNγ-诱导的细胞死亡和cGAS-STING激活，并显着改善抗肿瘤效果和免疫治疗反应。通过基因组尺度的遗传相互作用筛选，该课题组人员发现BAK是VDAC2缺陷诱导效应的中介。从机制上讲，IFNγ刺激增加了BIM、BID和BAK的表达，VDAC2缺乏引起IFNγ诱导的不受控制的BAK激活和线粒体损伤。因此，线粒体DNA被异常释放到细胞质中，并触发cGAS-STING信号和I型IFN反应的自动激活。重要的是，STING信号成分的共同缺失抑制了VDAC2在肿瘤细胞中的治疗效果，这表明靶向VDAC2将CD8⁺ T细胞和IFNγ介导的适应性免疫与肿瘤固有的先天免疫样反应结合起来。总之，他们的发现揭示了VDAC2作为克服肿瘤免疫逃避的双重作用靶点，并确立了协调破坏和炎症肿瘤以使癌症免疫治疗有效的重要性。

据介绍，肿瘤细胞经常逃避CD8⁺ T细胞或免疫疗法施加的免疫压力，其机制在很大程度上尚不清楚。

附：英文原文

Title: VDAC2 loss elicits tumour destruction and inflammation for cancer therapy

Author: 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

Issue&Volume: 2025-03-19

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.

DOI: 10.1038/s41586-025-08732-6

Source: https://www.nature.com/articles/s41586-025-08732-6