Targeting cGAS-STING: From Genomic Instability to Cancer Immunity

Genomic instability is a hallmark of cancer, which promotes the occurrence, progression, and resistance to treatment of cancer by promoting the accumulation of genetic and epigenetic changes. In addition to promoting malignant transformation, genomic instability can also lead to abnormally localized DNA species, such as micronucleus DNA, chromosome fragments, and extrachromosomal DNA, which are recognized by the interferon gene promoter (STING) pathway. This pathway is regulated by cyclic GMP-AMP synthase (cGAS), which is the key axis of innate immune surveillance. The activation of the cGAS-STING pathway then triggers downstream transcriptional cascades, including the IRF3 signaling pathway and the NF-κB signaling pathway, which in turn up-regulates the expression of type I interferons, pro-inflammatory cytokines, and chemokines, and ultimately promotes anti-tumor immune responses. However, more and more evidence shows that the cGAS-STING pathway has a significant dual role in cancer progression, which means that cGAS-STING is intertwined with complex nonlinear networks in different cell types and different stages of cancer development. Therefore, elucidating the spatiotemporal regulation mechanism of the cGAS-STING axis and its downstream effectors in different stages of tumorigenesis, malignant progression, metastasis and diffusion has become a key research priority. Based on the above considerations, this paper reviews the existing knowledge about the interaction between the cGAS-STING axis and genomic instability and cancer immunity, especially focusing on the mechanism basis of its abnormal regulation, potential therapeutic value, and the urgent need to adopt precise guidance strategies to identify individuals most likely to benefit from treatment for this pathway.