Tumor endothelial cells as vascular immune gatekeepers: reprogramming the vascular-immune interface for cancer...

Despite durable clinical responses to immunotherapy in a subset of patients, most solid tumors remain refractory owing to an immune-excluded phenotype characterized by limited trafficking, infiltration, and function of effector immune cells within the tumor microenvironment (TME). Tumor endothelial cells (TECs) function as vascular immune gatekeepers that orchestrate this process. Driven by persistent pro-angiogenic signaling and metabolic stress, TECs establish a multilayered immune barrier through structurally abnormal, poorly perfused vasculature, endothelial anergy, and active immunosuppressive programs. TECs directly suppress effector T-cell and natural killer (NK)-cell function through checkpoint-like ligands, death-ligand pathways, and immunometabolic mechanisms involving adenosine production and tryptophan catabolism. Simultaneously, they recruit, retain, and reprogram immunosuppressive leukocytes, thereby reinforcing immune exclusion and therapeutic resistance. Here, we propose a TEC-centric vascular immune gatekeeping framework and review strategies to reprogram tumor vessels from immune barriers into conduits for effective immune-cell trafficking and activation. We discuss endothelial-directed monotherapies that transiently normalize or reset TEC states, together with combination strategies integrating vascular modulation with immune checkpoint blockade, adoptive and innate immune-cell therapies, cancer vaccines, oncolytic viruses, STING agonists, and multifunctional antibodies. We also highlight key translational considerations, including biomarker-guided patient stratification, pharmacodynamic monitoring using mechanism-based endpoints, and optimization of treatment dose and scheduling within the vascular normalization window. Overall, this review establishes endothelial reprogramming as a central strategy for overcoming vascular immune gatekeeping and provides a mechanistic framework for biomarker-guided vascular-immune combination therapies in solid tumors.