癌症中的DNA感应:cGAS-STING信号传导的促肿瘤和抗肿瘤功能。
DNA sensing in cancer: Pro-tumour and anti-tumour functions of cGAS-STING signalling.
发表日期:2023 Aug 03
作者:
Otto P G Wheeler, Leonie Unterholzner
来源:
CYTOKINE & GROWTH FACTOR REVIEWS
摘要:
DNA传感器cGAS(环GMP-AMP合酶)及其适配蛋白STING(干扰素基因刺激剂)能够检测细胞质DNA的存在,作为感染或损伤的标志。在癌细胞中,通过持久的DNA损伤和染色体不稳定性,可激活该途径,导致微核的形成和DNA片段暴露于细胞质中。放疗或化疗引起的DNA损伤可进一步激活DNA感应反应,此反应可发生在癌细胞自身或肿瘤微环境(TME)中的基质和免疫细胞中。 cGAS-STING信号通路导致Ⅰ型干扰素的产生,已与易受免疫监测和免疫治疗方法影响的“热”肿瘤中的免疫细胞浸润联系起来。然而,最新的研究强调了STING信号转导的复杂性,肿瘤发展出了机制来逃避和利用这种信号通路以获益。在这篇小综述中,我们将探讨TME中不同细胞中的cGAS-STING信号转导如何促进抗肿瘤和促肿瘤反应。这包括Ⅰ型干扰素和细胞内第二信使cGAMP在TME中的作用,以及STING信号对局部免疫细胞种群的影响。我们还将研究STING下游的替代信号级联如何促进慢性干扰素信号转导、转录因子核因子κ倍升增活化B细胞(NF-κB)的激活以及促炎因子的产生,这些因素可能具有促进肿瘤的功能。需要深入了解不同细胞环境中的DNA感应,以发挥STING信号转导的抗肿瘤功能。© 2023 作者。
The DNA sensor cGAS (cyclic GMP-AMP synthase) and its adaptor protein STING (Stimulator of Interferon Genes) detect the presence of cytosolic DNA as a sign of infection or damage. In cancer cells, this pathway can be activated through persistent DNA damage and chromosomal instability, which results in the formation of micronuclei and the exposure of DNA fragments to the cytosol. DNA damage from radio- or chemotherapy can further activate DNA sensing responses, which may occur in the cancer cells themselves or in stromal and immune cells in the tumour microenvironment (TME). cGAS-STING signalling results in the production of type I interferons, which have been linked to immune cell infiltration in 'hot' tumours that are susceptible to immunosurveillance and immunotherapy approaches. However, recent research has highlighted the complex nature of STING signalling, with tumours having developed mechanisms to evade and hijack this signalling pathway for their own benefit. In this mini-review we will explore how cGAS-STING signalling in different cells in the TME can promote both anti-tumour and pro-tumour responses. This includes the role of type I interferons and the second messenger cGAMP in the TME, and the influence of STING signalling on local immune cell populations. We examine how alternative signalling cascades downstream of STING can promote chronic interferon signalling, the activation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and the production of inflammatory cytokines, which can have pro-tumour functions. An in-depth understanding of DNA sensing in different cell contexts will be required to harness the anti-tumour functions of STING signalling.© 2023 The Author(s).