Extended Data Fig. 11: Mechanism of action of the identified STING antagonists.

In the absence of inhibition, ligand binding triggers the translocation of STING to the Golgi^1,25, where palmitoylation occurs at cytoplasmic proximal cysteine residues (Cys88 and Cys91)²⁶. In turn, this post-translational modification facilitates the multimerization of STING to create a platform—possibly at the lipid raft domain at the trans-Golgi network²⁶—for the recruitment of TBK1, and thereby enables the initiation of downstream signalling. Through covalent interaction with Cys91, the compounds we describe here block the palmitoylation of STING and retain the protein in a signalling-incompetent state.