At the Crossroads of the cGAS-cGAMP-STING Pathway and the DNA Damage Response: Implications for Cancer Progression and Treatment

Abstract

The evolutionary conserved DNA-sensing cGAS-STING innate immunity pathway represents one of the most important cytosolic DNA-sensing systems that is activated in response to viral invasion and/or damage to the integrity of the nuclear envelope. The key outcome of this pathway is the production of interferon, which subsequently stimulates the transcription of hundreds of genes. In oncology, the situation is complex because this pathway may serve either anti- or pro-oncogenic roles, depending on context. The prevailing understanding is that when the innate immune response is activated by sensing cytosolic DNA, such as DNA released from ruptured micronuclei, it results in the production of interferon, which attracts cytotoxic cells to destroy tumors. However, in tumor cells that have adjusted to significant chromosomal instability, particularly in relapsed, treatment-resistant cancers, the cGAS–STING pathway often supports cancer progression, fostering the epithelial-to-mesenchymal transition (EMT). Here, we review this intricate pathway in terms of its association with cancer progression, giving special attention to pancreatic ductal adenocarcinoma and gliomas. As the development of new cGAS–STING-modulating small molecules and immunotherapies such as oncolytic viruses involves serious challenges, we highlight several recent fundamental discoveries, such as the proton-channeling function of STING. These discoveries may serve as guiding lights for potential pharmacological advancements.

Oncogenic BRCA1,2 Mutations in the Human Lineage—A By-Product of Sexual Selection?

“…Additionally, the mechanisms in familial BC might involve proteins interacting with BRCA1 and BRCA2. Another hypothetical mechanism could involve unresolved R-loops in mutation carriers, leading to chronic activation of the cGAS-STING nucleic acid sensing pathway (reviewed, for example, in [86]). Normally, this pathway is a potent oncosuppressor when it is excited in an acute mode, while its chronic activity can cause overstimulation of surrounding tissues and immune cells by interferons, leading to tachyphylaxis and continuous non-canonical NF-kB pathway activation in malignant cells.…”