The crosstalk between lymphatic endothelial cells and immune cells in Physiological and Pathological conditions

The lymphatic system serves two primary functions: the absorption of interstitial fluid and the coordination of immune cell interactions and transport. Central to these roles is the dynamic interplay between lymphatic endothelial cells (LECs) and immune cells, which acts as a critical hub for maintaining physiological homeostasis and regulating pathological processes. Under physiological conditions, LECs orchestrate immune responses by establishing chemokine gradients, modulating the metabolic microenvironment, and expressing adhesion molecules. They collaborate with dendritic cells (DCs) to initiate immunity, finely regulate the differentiation and homing of T cell subsets, support B cell-mediated humoral immunity, and work with macrophages to maintain tissue homeostasis. In pathological states, LECs assume a dual role. In inflammatory diseases, such as infections and autoimmune disorders, they recruit immune cells through the secretion of pro-inflammatory cytokines to clear pathogens; conversely, their aberrant antigen presentation may break immune tolerance and promote the activation of autoreactive T and B cells. During cancer progression, tumor-associated LECs adopt context-dependent programs, either constructing immunosuppressive networks that facilitate immune evasion, lymphatic metastasis and resistance to immunotherapy, or supporting antigen transport and presentation that promote antitumor immunity. This review systematically elucidates the molecular mechanisms and translational implications of the interactions between LECs and immune cells. It provides a theoretical foundation for precision therapies targeting the lymphatic-immune network. The insights garnered not only enhance our understanding of the mechanisms underlying disease pathogenesis but also unveil novel therapeutic avenues for targeting inflammatory diseases and cancer, holding significant value for both basic research and clinical translation.