SLC19A1 is a plasma membrane antiporter that mediates the bidirectional transport of reduced folates and cyclic dinucleotides (CDNs), coupling substrate import to the export of intracellular organic anions. The transporter exhibits high affinity for N5-methyltetrahydrofolate, the predominant circulating form of folate, and also transports the antifolate drug methotrexate. Beyond folate metabolism, SLC19A1 serves as the major cellular importer of immunoreactive CDNs, including 2'3'-cGAMP, a second messenger produced by cytosolic DNA sensors 1. By facilitating CDN entry, SLC19A1 enables activation of the cGAS-STING pathway and downstream type I interferon responses, linking nutrient transport to innate immunity 2. Structurally, SLC19A1 uses distinct recognition mechanisms for different substrates: CDNs bind as dimers in the inward-open conformation but as monomers in the outward-open state, whereas folates and antifolates occupy separate pockets within the transport cavity 3. The transporter's role in methotrexate accumulation makes it clinically relevant for cancer therapy; loss-of-function variants correlate with methotrexate resistance in human cancers 4. Pathogenic SLC19A1 variants associate with multiple disorders, including immunodeficiency 114 (folate-responsive), cerebral folate deficiency, and neural tube defects. In autism spectrum disorder patients with cerebral folate deficiency, the rs1051266 variant modifies disease severity and folate metabolism markers 5. In metastatic colorectal cancer, SLC19A1 polymorphisms predict irinotecan-plus-fluoropyrimidine response rates 6, and methotrexate efficacy and toxicity are influenced by SLC19A1 genetic polymorphisms 7.