Triggers of cGAS–STING signaling pathway. The cGAS–STING signal can be activated by exogenous DNA, extracellular self‐DNA, mitochondrial DNA, intranuclear genomic DNA, and micronucleus DNA (red font). Exogenous DNA is mainly derived from DNA viruses, bacteria, and parasites, which can also be encapsulated into vesicles to trigger cGAS in bystanders and adjacent cells via paracrine diffusion. In addition, retroviruses, with the assistance of NONO, bring cGAS to the site that HIV integrates and replicates in the nucleus, resulting in cGAS sensing HIV reverse‐transcribed DNA in the nucleus. PQBP1 promotes the interaction of ssDNA from RNA virus reverse transcription with cGAS to activate STING signal efficiently. Extracellular self‐DNA: increased nonapoptotic cell death, such as tumor cell necrosis, promotes its DNA to be encapsulated into vesicles into bystanders or adjacent cells. Mitochondrial DNA: RNA viruses, IL‐1β, and IFN‐α induce mitochondrial stress, resulting in the exposure of mitochondrial DNA into the cytoplasm to be sensed by cGAS. Intranuclear genomic DNA: when organisms are exposed to environmental stimuli such as reactive oxygen species (ROS) or ultraviolet (UV) radiation, genomic DNA in the nucleus may be damaged, and the leakage of damaged DNA into the cytoplasm triggers the activation of cGAS. During mitosis in proliferating cells, cGAS enters the nucleus and binds to chromatin DNA. However, the interaction of cGAS with chromatin is not or is not only mediated by DNA but may also involve protein‐protein interactions, which may be the key to preventing GAS activation. Micronucleus DNA: irreversible mitotic DNA damage, chromosome missegregation, or other DNA replication problems usually result in the formation of a micronucleus at the end of mitosis. However, the micronucleus membrane is fragile and easily ruptured, resulting in the exposure of micronucleus DNA to the cytoplasm. NONO, non‐POU domain‐containing octamer binding protein; PQBP1, polyglutamine binding protein 1; IL‐1β, interleukin‐1β
