Polyamine sequestration of 2′3′-cGAMP constrains intercellular transmission and STING engagement to subvert antitumor immunity

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Abstract

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.

Authors

Yunjin Ma, Chunyuan Zhao, Jiacheng Guo, Yue Fu, Wei Wang, Jiangong Zhang, Kun Zhao, Xiangbo Meng, Zhongshang Yuan, Chengjiang Gao, Mutian Jia, Ying Qin, Hui Song, Wei Zhao