Targeting Metabolic Pathways to Direct T-Cell Trafficking: Therapeutic Perspectives

Despite advances in immunomodulatory therapies, dysregulated T-cell trafficking persists as a pathological cornerstone in chronic inflammation, autoimmunity, and cancer. This spatially precise navigation-orchestrated by receptor-ligand cascades-ensures immune surveillance but drives disease when impaired. Targeting individual receptors faces limitations due to functional redundancy. Emerging research establishes metabolic reprogramming as a critical regulator of trafficking efficiency, where glucose, amino acid, lipid, and mitochondrial metabolism dynamically control all stages: from chemotaxis, selectin-mediated rolling, and integrin-dependent adhesion to transendothelial migration and interstitial migration. Critically, these pathways integrate energy supply, metabolite signaling, and epigenetic modulation to influence T-cell trafficking fates. Here, we dissect how reprogramming core metabolic networks calibrates trafficking cascades and highlight therapeutic strategies targeting key nodes to correct pathological migration in autoimmunity, cancer, and transplantation.