Oleic Acid Dissolves cGAS–DNA Phase Separation to Inhibit Immune Surveillance

Phase separation (PS) is a fundamental principle in diverse life processes including immunosurveillance. Despite numerous studies on PS, little is known about its dissolution. Here, it is shown that oleic acid (OA) dissolves the cyclic GMP–AMP synthase (cGAS)–deoxyribonucleic acid (DNA) PS and inhibits immune surveillance of DNA. As solvent components control PS and metabolites are abundant cellular components, it is speculated that some metabolite(s) may dissolve PS. Metabolite‐screening reveals that the cGAS–DNA condensates formed via PS are markedly dissolved by long‐chain fatty acids, including OA. OA revokes intracellular cGAS–PS and DNA‐induced activation. OA attenuates cGAS‐mediated antiviral and anticancer immunosurveillance. These results link metabolism and immunity by dissolving PS, which may be targeted for therapeutic interventions.