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 α-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 α-mangostin binds to and activates human STING, leading to activation of the downstream interferon regulatory factor (IRF) pathway and production of type I interferons. Furthermore, our studies show that α-mangostin has the potential to repolarize human monocyte-derived M2 macrophages to the M1 phenotype. The agonist effect of α-mangostin in the STING pathway might account for its antitumor and antiviral activities.