Second messenger 2′3′-cyclic GMP–AMP (2′3′-cGAMP): Synthesis, transmission, and degradation

Cyclic GMP-AMP synthase (cGAS) senses foreign DNA to produce 2'3'-cyclic GMP-AMP (2'3'-cGAMP). 2'3'-cGAMP is a second messenger that binds and activates the adaptor protein STING, which triggers the innate immune response. As a STING agonist, the small molecule 2'3'-cGAMP plays pivotal roles in antiviral defense and has adjuvant applications, and anti-tumor effects. 2'3'-cGAMP and its analogs are thus putative targets for immunotherapy and are currently being testedin clinical trials to treat solid tumors. However, several barriers to further development have emerged from these studies, such as evidence of immune and inflammatory side-effects, poor pharmacokinetics, and undesirable biodistribution. Here, we review the status of 2'3'-cGAMP research and outline the role of 2'3'-cGAMP in immune signaling, adjuvant applications, and cancer immunotherapy, as well as various 2'3'-cGAMP detection methods.