Slc1a2-mediated Glutamate Transport Promotes Dendritic Cell Immunity through Sema3A-regulated Cytoskeletal Remodeling and Migration.

Dendritic cells (DCs) can activate T cells to trigger sustained antitumor immune responses, a process in which the continuous migration of antigen-loaded DCs from the tumor microenvironment to tumor-draining lymph nodes is critical. DCs have evolved a complex and dynamic regulatory network to mediate their migration to specific locations, with multiple transporters including amino acid transporters reported to participate in this process. Slc1a2 is highly expressed in the nervous system, where it mediates the clearance of extracellular glutamate, primarily in astrocytes; however, its role in the immune system remains unclear. In this study, we showed that activated DCs upregulated Slc1a2 to boost glutamate uptake, which in turn promoted DC functionality and antitumor vaccine potency. Furthermore, glutamate signaling induced Sema3A, which elevated small GTPase signaling pathways (e.g., RhoA/Rac1/Cdc42) and drove dynamic cytoskeletal remodeling, thereby providing the necessary molecular machinery for DC migration during antitumor immunity in vivo. We first demonstrated that Slc1a2-mediated glutamate metabolism functioned as a metabolic checkpoint for DC migration and antigen-specific immunity in vivo, with the Sema3A/small GTPase axis serving as the core mechanism linking glutamate signaling to cytoskeletal reorganization.