The cyclic dinucleotide 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP) serves as a central immunotransmitter that propagates stimulator of interferon gene-dependent (STING-dependent) innate immunity across tissues; however, how microenvironmental metabolites regulate its spatiotemporal dynamics remains unknown. Here, we identified polyamines (spermine and spermidine) as critical rheostats controlling 2'3'-cGAMP functionality. Mechanistically, polyamines sequestered 2'3'-cGAMP into polymer-like aggregates, blocking intercellular propagation and suppressing intracellular STING activation by reducing ligand-receptor binding affinity. Deficiency of spermidine and spermine N1-acetyltransferase 1 (SAT1), the rate-limiting enzyme in polyamine catabolism, elevated polyamine levels to entrap extracellular 2'3'-cGAMP and inhibit STING activation. Synergistic administration of endogenous 2'3'-cGAMP with SAT1 stabilizer N1,N11-diethylnorspermine restored 2'3'-cGAMP bioavailability and STING signaling, facilitated type I interferon responses to reprogram immunologically suppressive tumors into immunologically active states and enhanced tumor clearance. Our study established polyamine-cGAMP interactions as a critical spatiotemporal regulatory mechanism for tissue-level immunity, providing a unified model for metabolite-mediated cyclic GMP-AMP synthase-STING (cGAS-STING) regulation across diseases.
Ma et al. (Mon,) studied this question.