C-178, a covalent inhibitor of STING, binds to Cys91, potently and selectively suppresses the STING responses elicited by distinct bona fide activators in mouse but not human. C-178 significantly reduces STING-, but not RIG-I- or TBK1-, mediated IFN-β reporter activity. C-178 blocks palmitoylation (PMA)-induced clustering of STING; inhibits the CMA-induced phosphorylation of TBK1 (downstream protein kinase of STING).