The LRRC8A:C Heteromeric Channel Is a cGAMP Transporter and the Dominant cGAMP Importer in Human Vasculature Cells

Abstract

SUMMARY Extracellular 2’3’-cyclic-GMP-AMP (cGAMP) is an immunotransmitter secreted by cancer cells and taken up by host cells to activate the anti-cancer STING pathway. No cGAMP exporter has been identified, and SLC19A1, a recently identified cGAMP importer, does not account for the import activity in most cell types. Here, we identify the LRRC8A:C heteromeric channel, a volume-regulated anion channel (VRAC), as a cGAMP transporter. This channel mediates cGAMP import or export depending on the cGAMP chemical gradient, and channel activation or inhibition modulates cGAMP transport. Other 2’3’-cyclic dinucleotides are also transported by LRRC8A:C channels, including the investigational cancer therapeutic ADU-S100. Furthermore, we demonstrate that the LRRC8A-containing channel is the dominant cGAMP importer in primary human vasculature cells. Given tumor vasculature’s regulation of immune infiltration and its disruption in response to STING agonists, we have uncovered a leading molecular mechanism for extracellular cGAMP signaling in this important anti-cancer target.