Lymphatic Endothelial Cells in Health and Disease.

Lymphatic endothelial cells (LECs) line the lymphatic vasculature and support interstitial fluid drainage, lipid transport, and immune-cell trafficking. Beyond these classical functions, recent studies now recognize LECs as heterogeneous, spatially organized endothelial regulators that maintain lymphatic identity while adopting tissue-, segment-, and disease-associated states. Advances in lineage tracing, multiomics, functional imaging, and perturbation studies now link LEC heterogeneity to drainage control, immune surveillance, antigen handling, metabolic homeostasis, and tissue repair. Despite these advances, a unified framework explaining how developmental origin, tissue niche, and context-dependent state transitions collectively shape LEC function across physiology and disease remains lacking. In this review, we summarize the developmental origins, identity-maintenance mechanisms, and anatomical deployment of LEC states across the lymphatic network. We then discuss how specialized LEC states coordinate lymphatic transport, immune surveillance, and peripheral tolerance under homeostasis. We further examine how context-dependent LEC reprogramming contributes to lymphatic disorders, inflammation and autoimmunity, cancer, cardiometabolic disease, and central nervous system dysfunction. Finally, we highlight challenges and opportunities for translational LEC-targeted therapy. Together, this state-centered framework reframes LECs as actionable regulators of tissue homeostasis and disease progression, providing a conceptual foundation for precision lymphatic medicine.