Autophagy in lymphatic endothelial cells promotes lung metastasis

Summary Macroautophagy/autophagy is the main lysosomal pathway for the degradation and recycling of cytoplasmic cargo, with emerging roles in endothelial cell (EC) biology. While autophagy has been extensively studied in blood ECs, its function in lymphatic ECs (LECs) remains unexplored. Given the central role of the lymphatic system in antitumor immunity and metastatic spread, we investigated how LEC autophagy affects metastatic lung colonization. In line with previous reports showing that autophagy regulates the availability of the egress signal sphingosine 1 phosphate (S1P) in secondary lymphoid organs (SLOs), lungs of non-tumor-bearing mice with LEC-specific genetic deletion of Atg5 (ATG5 LEC-KO mice) exhibited reduced lymphocyte infiltration. Remarkably, in tumor-bearing mice, either genetic loss of LEC-autophagy or pharmacological blockade of S1P lyase by 4-deoxypyridoxine (DOP) suppressed lung metastasis. Pulmonary immune profiling revealed that while DOP enhanced effector T cell activity despite lower numbers, LEC-autophagy-deficient mice markedly increased the B and CD8 T Cell abundance coupled with profound reduction of VEGFR3 expression in the lung lymphatic vasculature. Together, these findings uncover an autophagy-dependent remodeling of the lymphatic routes and immune niches that fosters metastatic seeding and growth in the lung.