微核激活cGAS-STING信号通路的机制及其肿瘤免疫功能

Role of micronucleus-activated cGAS-STING signaling in antitumor immunity

环鸟苷酸-腺苷酸合成酶(cGAS)-干扰素基因刺激因子(STING)信号通路可监测微生物入侵和组织损伤等生理病理异常状态,是天然免疫系统的重要组成之一。作为DNA感受器,cGAS主要识别异常定位于细胞质的双链DNA(dsDNA),通过催化合成二级信使环鸟苷酸-腺苷酸启动由STING介导的Ⅰ型干扰素和炎症信号通路。微核是有丝分裂后期染色体错误分离的产物,也是细胞质dsDNA的重要来源之一。作为一类不稳定的亚细胞器结构,微核核膜倾向于不可逆的破裂,导致微核基因组DNA暴露在细胞质中。暴露的微核基因组DNA招募并激活cGAS-STING信号通路,诱导STING下游信号通路活化,包括Ⅰ型干扰素信号通路和经典核因子κB(NF-κB)信号通路,导致细胞衰老、细胞凋亡和细胞自噬的发生,从而介导免疫系统的活化以清除肿瘤细胞,或者直接诱导肿瘤细胞死亡。另外,STING持续激活诱导的内质网应激,以及慢性Ⅰ型干扰素信号通路和非经典NF-κB信号通路的活化,营造了免疫抑制的肿瘤微环境,导致肿瘤细胞免疫逃逸,促进肿瘤转移和肿瘤细胞存活。因此,在肿瘤的发生发展和治疗过程中,活化的cGAS-STING免疫通路扮演着抑制或促进肿瘤的双重作用。本文阐述了肿瘤微环境中微核诱导cGAS-STING免疫通路活化的机制研究进展,探讨了其在肿瘤发生发展和治疗中的潜在重要作用。

Cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)-stimulator of interferon genes(STING)signaling is a significant component of the innate immune system and functions as a vital sentinel mechanism to monitor cellular and tissue aberrations in microbial invasion and organ injury.cGAS,a cytosolic DNA sensor,is specialized in recognizing abnormally localized cytoplasmic doublestranded DNA(dsDNA)and catalyzes the formation of a second messenger cyclic-GMPAMP(cGAMP),which initiates a cascade of typeⅠinterferon and inflammatory responses mediated by STING.Micronucleus,a byproduct of chromosomal missegregation during anaphase,is also a significant contributor to cytoplasmic dsDNA.These unstable subcellular structures are susceptible to irreversible nuclear envelope rupture,exposing genomic dsDNA to the cytoplasm,which potently recruits cGAS and activates STING-mediated innate immune signaling and its downstream activities,including typeⅠinterferon and classical nuclear factor-κB(NF-κB)signaling pathways lead to senescence,apoptosis,autophagy activating anti-cancer immunity or directly killing tumor cells.However,sustained STING activation-induced endoplasmic reticulum stress,activated chronic typeⅠinterferon and nonclassical NF-κB signaling pathways remodel immunosuppressive tumor microenvironment,leading to immune evasion and facilitating tumor metastasis.Therefore,activated cGAS-STING signaling plays a dual role of suppressing or facilitating tumor growth in tumorigenesis and therapy.This review elaborates on research advances in mechanisms of micronucleus inducing activation of cGAS-STING signaling and its implications in tumorigenesis and therapeutic strategies of malignant tumors.