Targeting the CD31 Immunometabolic Axis: Precision Strategies for Modulating T Cell Activation, Migration, and Autophagy

CD31 (PECAM-1) is broadly expressed on endothelial cells, platelets, and immune cells, where it helps set thresholds for immune activation and coordinates energy use. This Review synthesizes evidence that CD31 is a key regulator of immunometabolic pathways relevant to metabolic disease. We outline how CD31 restrains T-cell activation, guides T-cell migration, and adjusts metabolic reprogramming by balancing glycolysis with mitochondrial function to fine-tune effector responses. We also describe how CD31-dependent signaling at the vascular-immune interface shapes tissue inflammation in obesity, diabetes, and atherosclerosis. Both membrane CD31 and its soluble form (sCD31) show promise as biomarkers and as therapeutic entry points, and we summarize emerging strategies to modulate this pathway. We highlight outstanding challenges including pathway complexity, context dependence, and inter-individual variability that must be addressed to achieve clinical translation. By linking molecular mechanisms to disease phenotypes, this Review positions CD31 as a unifying node connecting vascular and immune control with metabolism, pointing to testable avenues for precision treatment of metabolic inflammation.