Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, U.K.
Biochem Soc Trans. 2023 Apr 26;51(2):539-555. doi: 10.1042/BST20220838.
Chromosomal instability (CIN) is a hallmark of cancer that drives tumour evolution. It is now recognised that CIN in cancer leads to the constitutive production of misplaced DNA in the form of micronuclei and chromatin bridges. These structures are detected by the nucleic acid sensor cGAS, leading to the production of the second messenger 2'3'-cGAMP and activation of the critical hub of innate immune signalling STING. Activation of this immune pathway should instigate the influx and activation of immune cells, resulting in the eradication of cancer cells. That this does not universally occur in the context of CIN remains an unanswered paradox in cancer. Instead, CIN-high cancers are notably adept at immune evasion and are highly metastatic with typically poor outcomes. In this review, we discuss the diverse facets of the cGAS-STING signalling pathway, including emerging roles in homeostatic processes and their intersection with genome stability regulation, its role as a driver of chronic pro-tumour inflammation, and crosstalk with the tumour microenvironment, which may collectively underlie its apparent maintenance in cancers. A better understanding of the mechanisms whereby this immune surveillance pathway is commandeered by chromosomally unstable cancers is critical to the identification of new vulnerabilities for therapeutic exploitation.
染色体不稳定性（CIN）是癌症的一个标志，它推动了肿瘤的进化。现在人们认识到，癌症中的 CIN 导致以微核和染色质桥形式出现的错位 DNA 的持续产生。这些结构被核酸传感器 cGAS 检测到，导致第二信使 2'3'-cGAMP 的产生，并激活先天免疫信号转导的关键枢纽 STING。这种免疫途径的激活应该会引发免疫细胞的涌入和激活，从而导致癌细胞的清除。然而，在 CIN 的背景下，这种情况并非普遍存在，这仍然是癌症中一个未解决的悖论。相反，CIN 高的癌症显然擅长免疫逃避，并且具有高度的转移性，通常预后不良。在这篇综述中，我们讨论了 cGAS-STING 信号通路的多个方面，包括其在稳态过程中的新兴作用及其与基因组稳定性调节的交叉，它作为慢性促肿瘤炎症驱动因素的作用，以及与肿瘤微环境的串扰，这些可能共同构成了其在癌症中明显维持的基础。更好地理解这种免疫监视途径如何被染色体不稳定的癌症所利用，对于确定新的治疗靶点至关重要。
