Targeting the loss of cGAS/STING signaling in cancer.

Abstract

The cGAS/STING pathway provides a key host defense mechanism by detecting the accumulation of cytoplasmic double-stranded DNA (dsDNA) and mediating innate and adaptive immune signaling. In addition to detecting pathogen-derived dsDNA, cGAS senses intrinsic dsDNA, such as those associated with defective cell cycle progression and mitophagy that has leaked from the nucleus or mitochondria, and subsequently evokes host immunity to eliminate pathogenic cells. In cancer cells, dysregulation of DNA repair and cell cycle caused at the DNA replication checkpoint and spindle assembly checkpoint results in aberrant cytoplasmic dsDNA accumulation, stimulating anti-tumor immunity. Therefore, the suppression of cGAS/STING signaling is beneficial for survival and frequently observed in cancer cells as a way to evade detection by the immune system, and is likely to be related to immune checkpoint blockade (ICB) resistance. Indeed, the mechanisms of ICB resistance overlap with those acquired in cancers during immunoediting to evade immune surveillance. This review highlights the current understanding of cGAS/STING suppression in cancer cells and discusses how to establish effective strategies to regenerate effective anti-tumor immunity through reactivation of the cGAS/STING pathway.