Chromosomal instability (CIN) drives cancer cell evolution, metastasis and therapy resistance, and is associated with poor prognosis¹. CIN leads to micronuclei that release DNA into the cytoplasm after rupture, which triggers activation of inflammatory signalling mediated by cGAS and STING^2,3. These two proteins are considered to be tumour suppressors as they promote apoptosis and immunosurveillance. However, cGAS and STING are rarely inactivated in cancer⁴, and, although they have been implicated in metastasis⁵, it is not known why loss-of-function mutations do not arise in primary tumours⁴. Here we show that inactivation of cGAS–STING signalling selectively impairs the survival of triple-negative breast cancer cells that display CIN. CIN triggers IL-6–STAT3-mediated signalling, which depends on the cGAS–STING pathway and the non-canonical NF-κB pathway. Blockade of IL-6 signalling by tocilizumab, a clinically used drug that targets the IL-6 receptor (IL-6R), selectively impairs the growth of cultured triple-negative breast cancer cells that exhibit CIN. Moreover, outgrowth of chromosomally instable tumours is significantly delayed compared with tumours that do not display CIN. Notably, this targetable vulnerability is conserved across cancer types that express high levels of IL-6 and/or IL-6R in vitro and in vivo. Together, our work demonstrates pro-tumorigenic traits of cGAS–STING signalling and explains why the cGAS–STING pathway is rarely inactivated in primary tumours. Repurposing tocilizumab could be a strategy to treat cancers with CIN that overexpress IL-6R.

染色体不稳定性 (CIN) 驱动癌细胞进化、转移和治疗耐药性，并与不良预后相关¹。CIN 导致微核在破裂后将 DNA 释放到细胞质中，从而触发由 cGAS 和 STING 介导的炎症信号传导^2,3。这两种蛋白质被认为是肿瘤抑制因子，因为它们促进细胞凋亡和免疫监视。然而，cGAS 和 STING 很少在癌症中失活⁴，并且尽管它们与转移有关⁵，但尚不清楚为什么原发性肿瘤中不会出现功能丧失突变⁴. 在这里，我们表明 cGAS–STING 信号的失活会选择性地损害显示 CIN 的三阴性乳腺癌细胞的存活。CIN 触发 IL-6–STAT3 介导的信号传导，这取决于 cGAS–STING 通路和非经典 NF-κB 通路。托珠单抗是一种临床使用的靶向 IL-6 受体 (IL-6R) 的药物，可阻断 IL-6 信号传导，选择性地损害表现出 CIN 的培养的三阴性乳腺癌细胞的生长。此外，与不显示 CIN 的肿瘤相比，染色体不稳定肿瘤的生长显着延迟。值得注意的是，这种可靶向的脆弱性在体外和体内表达高水平 IL-6 和/或 IL-6R 的癌症类型中是保守的。一起，我们的工作证明了 cGAS–STING 信号通路的致瘤性特征，并解释了为什么 cGAS–STING 通路在原发性肿瘤中很少失活。重新利用托珠单抗可能是治疗过度表达 IL-6R 的 CIN 癌症的一种策略。