Identification of -Mangostin as an Agonist of Human STING

The xanthone derivate 5,6-dimethylxanthenone-4-acetic acid (DMXAA, also known as ASA404 or vadimezan) is a potent agonist of murine STING (stimulator of interferon genes), but cannot activate human STING. Herein we report that -mangostin, which bears the xanthone skeleton, is an agonist of human STING, but activates murine STING to a lesser extent. Biochemical and cell-based assays indicate that -mangostin binds to and activates human STING, leading to activation of the downstream interferon regulatory factor (IRF) pathway and production of typeI interferons. Furthermore, our studies show that -mangostin has the potential to repolarize human monocyte-derived M2 macrophages to the M1 phenotype. The agonist effect of -mangostin in the STING pathway might account for its antitumor and antiviral activities.