The mechanisms by which hypoxic tumours evade immunological pressure and anti-tumour immunity remain elusive. Here, we report that two hypoxia-responsive microRNAs, miR-25 and miR-93, are important for establishing an immunosuppressive tumour microenvironment by downregulating expression of the DNA sensor cGAS. Mechanistically, miR-25/93 targets NCOA3, an epigenetic factor that maintains basal levels of cGAS expression, leading to repression of cGAS during hypoxia. This allows hypoxic tumour cells to escape immunological responses induced by damage-associated molecular pattern molecules, specifically the release of mitochondrial DNA. Moreover, restoring cGAS expression results in an anti-tumour immune response. Clinically, decreased levels of cGAS are associated with poor prognosis for patients with breast cancer harbouring high levels of miR-25/93. Together, these data suggest that inactivation of the cGAS pathway plays a critical role in tumour progression, and reveal a direct link between hypoxia-responsive miRNAs and adaptive immune responses to the hypoxic tumour microenvironment, thus unveiling potential new therapeutic strategies.

中文翻译：

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miR-25 / 93通过抑制cGAS介导低氧诱导的免疫抑制。

缺氧性肿瘤逃避免疫压力和抗肿瘤免疫的机制仍然难以捉摸。在这里，我们报告两个低氧反应性microRNA，miR-25和miR-93，对于通过下调DNA传感器cGAS的表达来建立免疫抑制性肿瘤微环境很重要。从机制上讲，miR-25 / 93靶向NCOA3，后者是一种维持cGAS表达基础水平的表观遗传因子，可导致缺氧时cGAS的抑制。这使缺氧的肿瘤细胞能够逃避由损伤相关分子模式分子诱导的免疫反应，特别是线粒体DNA的释放。而且，恢复cGAS表达导致抗肿瘤免疫应答。临床上 携带高水平miR-25 / 93的乳腺癌患者的cGAS水平降低与预后不良有关。总之，这些数据表明，cGAS途径的失活在肿瘤进展中起关键作用，并揭示了低氧反应性miRNA与对低氧肿瘤微环境的适应性免疫反应之间的直接联系，从而揭示了潜在的新治疗策略。