Abstract LB388: Innate immunity-independent roles of 2'3'-cGAMP in tumor metastasis control

Abstract c-di-GAMP was first identified in bacteria to promote colonization, while mammalian 2’3’-cGAMP is synthesized by cGAS to activate STING for innate immune stimulation. However, 2’3’-cGAMP function beyond innate immunity remains elusive. Here, we report 2’3’-cGAMP promotes cell migration independent of innate immunity. 2’3’-cGAMP interactome analysis identifies the small GTPase Rab18 as a 2’3’-cGAMP binding partner and effector in cell migration control. Mechanistically, 2’3’-cGAMP binds Rab18 to facilitate GTP loading and subsequent Rab18 activation, which further promotes FosB transcription in facilitating cell migration. Induced synthesis of endogenous 2’3’-cGAMP by intra-breast tumor bacterium S. aureus infection or low-dose doxorubicin treatment facilitates cell migration depending on the cGAS/cGAMP/Rab18/FosB signaling. Interestingly, we find lovastatin induces Rab18 deprenylation that abolishes 2’3’-cGAMP recognition therefore suppressing cell migration. Together, our study reveals a novel 2’3’-cGAMP function in cell migration control via the 2’3’-cGAMP/Rab18/FosB signaling that provides new insights into clinical applications of 2’3’-cGAMP. Citation Format: Pengda Liu, Yu Deng. Innate immunity-independent roles of 2'3'-cGAMP in tumor metastasis control [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB388.