Activation-induced SLC7A1 expression enhances T cell sensitivity to cGAMP-mediated STING signaling.

STING (stimulator of interferon genes) agonists are promising innate immune therapies and can be synergized with adaptive immune checkpoint blockade therapies for cancer treatment, but their effectiveness is limited by the toxicity to activated T cells. How STING agonists such as cGAMP and its analogs enter and induce STING activation and toxicity in T cells is unclear despite known transporters for other cell types. Here, we identify the cationic amino acid transporter SLC7A1 as a cGAMP transporter in activated primary mouse and human T cells. T cells upregulate this transporter upon activation to meet their high metabolic demand, but this comes at the cost of enabling increased transport and toxicity of cGAMP. We identified distinct residues in SLC7A1 that mediate cGAMP and arginine activity, suggesting that cGAMP transport may be separable from arginine uptake. These findings suggest that modulation of SLC7A1 may influence T cell susceptibility to cGAMP and its analogs.