Human SLC46A2 Is the Dominant cGAMP Importer in Extracellular cGAMP-Sensing Macrophages and Monocytes

Abstract

Administration of exogenous CDNs to activate the cGAMP-STING pathway is a promising therapeutic strategy to unleash the full potential of cancer immunotherapy. This strategy mirrors the role of endogenous extracellular cGAMP, an immunotransmitter that is transferred from cancer cells to cGAMP-sensing cells in the host, promoting immunity. However, the CDN import mechanisms used by host cells within tumors remain unknown. Here we identified the protein SLC46A2 as the dominant cGAMP importer in primary human monocytes. Furthermore, we discovered that monocytes and M1-polarized macrophages directly sense tumor-derived extracellular cGAMP in murine tumors. Finally, we demonstrated that SLC46A2 is the dominant cGAMP importer in monocyte-derived macrophages. Together, we provide the first cellular and molecular mechanisms of cGAMP as an immunotransmitter, paving the way for effective STING pathway therapeutics.

STING Agonists/Antagonists: Their Potential as Therapeutics and Future Developments

“…This strategy is very similar to activating STING or activating cGAS by blocking DNA degradation. It might also be possible to prevent the transport of cGAMP via some of the recently identified transporters [ 48 , 49 , 50 , 51 , 52 ]: this might prevent the spreading of activation of the pathway to adjacent cells [ 53 ] or else maintain a high level of cGAMP at the primary site of its synthesis. Preventing cGAMP transport might overlap, in some cases, with the effect of inhibition of STING or cGAS ( Figure 1 ).…”

ENPP1’s regulation of extracellular cGAMP is a ubiquitous mechanism of attenuating STING signaling

“…cGAMP was subsequently found to spread to neighboring cells through gap junctions ( 17 – 19 ) and exosomes ( 20 , 21 ), both of which do not permit access to the extracellular space. The prevailing view that cGAMP is exclusively an intracellular signal was challenged by the recent discovery that cGAMP is secreted into the extracellular space by cancer cells and functions as a paracrine immunotransmitter by entering and activating host immune cells ( 19 , 22 – 26 ). Intracellular cGAMP signaling is primarily regulated at the level of STING activation, which requires the formation of a large signaling complex ( 27 – 29 ) that has a high activation threshold but is irreversible once formed ( 27 ), explaining its role in uncontrolled inflammation.…”

“…Extracellular cGAMP signaling is controlled by many additional molecular and cellular mechanisms. cGAMP is transported by cell-type–specific transporters ( 25 , 26 , 30 – 33 ), allowing for cell-specific secretion and uptake. Additionally, extracellular cGAMP is degraded by the extracellular hydrolase ENPP1, while no intracellular cGAMP hydrolase has been reported ( 22 , 34 ).…”

Myeloid dysregulation and therapeutic intervention in COVID-19

“…Interestingly, cGAMP is not only a cell-intrinsic activator of STING, but also a paracrine mediator that orchestrates larger-scale biological responses. During viral infection, cGAMP can be exported directly to the extracellular space in a soluble, non-membrane bound form by LRRC8A:C/E heteromeric channels and imported into neighbor host cells by importers such as SLC19A1 and SLC46A2 [ [93] , [94] , [95] ].In particular, SLC46A2 represents the major cGAMP importer in primary human monocytes and monocyte-derived macrophages [ 95 ]. In the context of COVID-19, uncontrolled infection with SARS-CoV-2 in epithelial cells leads to pervasive cell damage and death [ 96 ], a process that likely triggers cGAS/STING activation and cGAMP release.…”