Spatial polarization of endothelial ICAM-1 governs T-cell exclusion in melanoma

Abstract An immunosuppressive microenvironment limits therapeutic efficacy in melanoma. Beyond T-cell abundance and function, tumor control depends on T-cell access to malignant cells, yet the vascular mechanisms governing T-cell positioning remain poorly defined. Using RNA sequencing of endothelial cells from tumor cores versus peripheries in a mouse melanoma model, we identified intercellular adhesion molecule-1 (ICAM-1) as a candidate regulator of T-cell localization. During tumor growth, T cells shifted from a balanced core-margin distribution to marked exclusion from the core, particularly in T cell-inflamed tumors. This spatial polarization, less evident in other immune subsets, coincided with high expression of lymphocyte function-associated antigen-1 (LFA-1) on T cells. Endothelial ICAM-1 became enriched at the tumor periphery, where vascular integrity was compromised, with increased vascular leakage and reduced pericyte coverage. ICAM-1 blockade restored T-cell infiltration, enhanced effector activity, and delayed growth of immunogenic tumors, and sensitized an immune-refractory tumor to anti-PD-1 blockade. These findings identify endothelial ICAM-1 as a vascular determinant of T-cell positioning and the ICAM-1/LFA-1 axis as a modifiable checkpoint to enhance antitumor immunity and immunotherapy efficacy.