The multifaceted role of cGAS-STING signalling in cancer progression and metastasization

The cGAS-STING pathway is an integral part of the innate immune system, responsible for initiating diverse responses that profoundly impact all facets of tumorigenesis, encompassing primary tumor survival and metastasis. Its activation in a tumor context can have both beneficial and detrimental outcomes, depending on the tumor type, the stage of development, and the microenvironment composition. Chromosomal instability, which is a driving force behind cancer cell evolution, metastasis, and therapy resistance, is the main activator of cGASSTING pathway in tumors. The formation of micronuclei, and the consequent generation of cytoplasmatic DNA, leads to the induction of the cGAS-STING pathway in cells exhibiting chromosomal instability, where it has been linked to enhanced metastatic behavior and increased survival. These effects can be attributed to the downstream activation of the noncanonical NF-kB pathway and the IL-6-STAT3 signaling. In contrast, in dormant metastases this pathway induces immune-mediated elimination of cancer cells through the activation of Type I Interferon signaling, suppressing metastatic outbreak and possible relapses. Despite its controversial role in cancer progression, pharmacological strategies targeting cGAS-STING pathway and its effectors have been proposed as a therapeutic approach for cancer patients. Understanding both the mechanisms of cGAS-STING activation and its influence on natural tumor-associated processes and cancer therapies is therefore crucial and asks for further investigations.