DNA is well-documented to stimulate immune response. However, the nature of the DNA to activate immune surveillance is less understood. Here, we show that the activation of cyclic GMP-AMP synthase (cGAS) depends on DNA mechanical flexibility, which is controlled by DNA-sequence, -damage and -length. Consistently, DNA-sequence was shown to control cGAS activation. Structural analyses revealed that a conserved cGAS residue (mouse R222 or human R236) contributed to the DNA-flexibility detection. And the residue substitution neutralised the flexibility-controlled DNA-potential to activate cGAS, and relaxed the DNA-length specificity of cGAS. Moreover, low dose radiation was shown to mount cGAS-mediated acute immune surveillance (AIS) via repairable (reusable) DNAs in hrs. Loss of cGAS-mediated AIS decreased the regression of local and abscopal tumours in the context of focal radiation and immune checkpoint blockade. Our results build a direct link between immunosurveillance and DNA mechanical feature.

DNA 被充分证明可以刺激免疫反应。然而，人们对 DNA 激活免疫监视的性质知之甚少。在这里，我们表明环 GMP-AMP 合酶 (cGAS) 的激活取决于 DNA 的机械灵活性，这是由 DNA 序列、损伤和长度控制的。一致地，DNA 序列被证明可以控制 cGAS 激活。结构分析显示保守的 cGAS 残基（小鼠 R222 或人类 R236）有助于 DNA 灵活性检测。并且残基取代中和了柔性控制的DNA潜力来激活cGAS，并放松了cGAS的DNA长度特异性。此外，低剂量辐射显示可在数小时内通过可修复（可重复使用）的 DNA 启动 cGAS 介导的急性免疫监视 (AIS)。在局灶性放射和免疫检查点阻断的情况下，cGAS 介导的 AIS 的缺失减少了局部和远端肿瘤的消退。我们的结果在免疫监视和 DNA 机械特征之间建立了直接联系。