在高等真核生物中，基因组功能的复杂调节要求所有染色体被装进单个细胞核。微核（MN）是一种解离性的类核结构，在衰老和多种疾病情况下经常观察到，具有重要但未被充分认识的病理生理功能。微核（MNi）最近被发现是胞内DNA的主要来源，可以通过细胞内途径激活cGAS-STING轴。但是，从不同的基因毒性压力诱导的MNi在结合或激活cGAS以及MN诱导的cGAS-STING轴下游信号响应方面显示出极大的异质性，包括自身免疫、自身炎症、转移或细胞死亡等不同结果。因此，全面表征支配cGAS和MN相互作用的分子网络对于阐明免疫原性MN的病理生理作用并设计通过增强MN衍生的cGAS-STING轴选择性靶向癌症的新药物是重要的。在这里，我们总结了我们对cGAS自身-DNA鉴定机制的当前理解。我们重点讨论了MN免疫原性是如何由多种机制决定的，包括微核膜完整性、核小体和DNA的状态、竞争因素、受损的线粒体DNA和微核吞噬作用。我们还描述了免疫原性MN和人类疾病（包括癌症、神经退行性疾病和COVID-19）之间的新兴联系。特别是，我们探讨了将免疫原性MN诱导作为治疗癌症的一种方法的令人兴奋的概念。我们提出了一个新的理论框架，将免疫原性MN描述为对基因毒性压力响应中细胞过程进行调节的生物传感器，并提供了发展新的实验方法以揭示MN免疫原性调控复杂性的观点。版权所有©2022 Elsevier B.V.

In higher eukaryotes, sophisticate regulation of genome function requires all chromosomes to be packed into a single nucleus. Micronucleus (MN), the dissociative nucleus-like structure frequently observed in aging and multiple disease settings, has critical, yet under-recognized, pathophysiological functions. Micronuclei (MNi) have recently emerged as major sources of cytosolic DNA that can activate the cGAS-STING axis in a cell-intrinsic manner. However, MNi induced from different genotoxic stressors display great heterogeneity in binding or activating cGAS and the signaling responses downstream of the MN-induced cGAS-STING axis have divergent outcomes including autoimmunity, autoinflammation, metastasis, or cell death. Thus, full characterization of molecular network underpinning the interplay of cGAS and MN is important to elucidate the pathophysiological roles of immunogenic MN and design improved drugs that selectively target cancer via boosting the MN-derived cGAS-STING axis. Here, we summarize our current understanding of the mechanisms for self-DNA discrimination by cGAS. We focus on discussing how MN immunogencity is dictated by multiple mechanisms including integrity of micronuclear envelope, state of nucleosome and DNA, competitive factors, damaged mitochondrial DNA and micronucleophagy. We also describe emerging links between immunogenic MN and human diseases including cancer, neurodegenerative diseases and COVID-19. Particularly, we explore the exciting concept of inducing immunogenic MN as a therapeutic approach in treating cancer. We propose a new theoretical framework to describe immunogenic MN as a biological sensor to modulate cellular processes in response to genotoxic stress and provide perspectives on developing novel experimental approaches to unravel the complexity of MN immunogenicity regulation and immunogenic MN pathophysiology.Copyright © 2022 Elsevier B.V. All rights reserved.