Autophagy in lymphatic endothelial cells promotes lung metastasis

Macroautophagy is well-characterized in blood endothelial cells but remains poorly defined in lymphatic endothelial cells (LECs). We previously showed that LEC-specific loss of Atg5 (autophagy-related 5; ATG5[LEC-KO]) impairs lymphocytes’ egress from secondary lymphoid organs (SLOs) by disrupting the sphingosine-1-phosphate (S1P) gradient, phenocopying S1P lyase blockade by 4-deoxypyridoxine (DOP). Here, we examined how these interventions affect lung metastasis. Both loss of ATG5 in LECs and DOP treatment suppressed melanoma lung colonization, but through distinct mechanisms. DOP reduced lymphocyte numbers but enhanced effector T cell function, consistent with improved immunosurveillance. Conversely, LEC-autophagy loss increased pulmonary B and CD8 T cell abundance and decreased FLT4/VEGFR3 (FMS-like tyrosine kinase 4) expression in LECs, indicating structural remodeling of the lymphatic network. These findings demonstrate that disruption of S1P metabolism or LEC-autophagy constrains metastasis via divergent modulation of lymphatic and immune compartments, underscoring LEC-autophagy as a non-redundant and targetable regulator of metastatic niche formation.