STINGDegrader-2 (Compound SI-43) is an inhibitor and mutant-specific degrader of STING. It effectively suppresses cGAMP-induced STING activation and significantly reduces the release of IFN-β and CXCL-10. By binding to two pockets of the STING dimer, it inhibits activity and induces proteasome-independent degradation of the mutant STINGS154 and STINGM155 (DC50 values of 0.31 and 0.76 μM, respectively). STINGDegrader-2 is applicable in the study of STING-related autoimmune diseases.