STING agonists/antagonists: their potential as therapeutics and future developments

The cGAS STING pathway has received much attention in the last years and it has been recognized as an important trigger of the innate immune response. Since the discovery of STING (in 2008) and later of cGAS (in 2013) there has been many reports suggesting that faulty regulation of this pathway is involved in many Type I IFN autoinflammatory disorders. Evidences have been accumulating that cGAS/STING might play an important role other pathologies beyond the classical immune diseases. Human genetic mutations, which result in the activation of STING, have been demonstrated as the driver of SAVI, a rare interferonopathy affecting young children. Nevertheless, no evidence is available in the clinics for the role of this pathway in a broader disease space, due to the lack of STING antagonists/antagonists that are qualified for clinical exploration. Hopes of quickly learning from STING agonists, which have reached clinical trials in the recent years for oncology indications (with mixed success) and of transforming these compounds in potent safe antagonists did not yet fulfill. Nevertheless, there has been progress in identifying novel compounds, showing in some cases unexpected mode of action, that might move to early clinical trials in the very near future. We will summarize current efforts in developing STING antagonists, describe their strength/weakness and discuss their potential for a STING drug