From repair to disease: lymphatic contributions to regeneration, cancer and ageing

BACKGROUND: The lymphatic vasculature maintains tissue fluid homeostasis, lipid transport, and immune surveillance. Beyond these classical roles, lymphatic vessels regulate tissue development and repair through lymphangiocrine signalling, whereby lymphatic endothelial cells (LECs) secrete mediators such as Reelin, R-spondin-3, and CCL21 that modulate stem cell niches, immune trafficking, and regeneration. Ageing-associated lymphatic dysfunction, driven by LEC senescence, impaired lymphangiogenesis, and lymph node stromal remodelling, leads to defective tissue repair, chronic low-grade inflammation, and increased susceptibility to diseases including cancer, cardiovascular disease, and neurodegeneration. AIM OF THE REVIEW: This review summarizes lymphangiocrine signalling in regeneration, ageing, and cancer, proposing that age-related LEC dysfunction drives disease through impaired drainage, immune dysregulation, and loss of regenerative niches, and discusses emerging lymphatic-targeted therapies. KEY SCIENTIFIC CONCEPTS: Lymphatic vessels function as multicellular signalling hubs composed of LECs and associated stromal and immune cells that coordinate immune and regenerative responses. We summarize organ-specific lymphangiocrine mechanisms across multiple tissues and their roles in stem cell regulation and tissue repair. Age-related changes in lymphatic vessels and lymph node stroma impair drainage, drive immune dysregulation and inflammaging, and reduce regenerative capacity. Dysregulated lymphangiocrine signalling contributes to diseases including lymphedema, cardiovascular and metabolic disorders, neurodegeneration, and cancer. Finally, we discuss emerging strategies to restore lymphatic function in ageing tissues.