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.