The tumor perivascular microenvironment in immune regulation: mechanisms, spatial heterogeneity, and therapeutic opportunities

The tumor vasculature is increasingly recognized as more than a passive conduit for oxygen and nutrient delivery; it constitutes a dynamic vascular niche that actively shapes antitumor immunity and therapeutic response. Recent advances in single-cell, spatial, and functional multi-omics have revealed that vascular abnormalities regulate immune states through coordinated changes in endothelial signaling, metabolism, and architecture. Here, we propose a unified framework in which the tumor vascular niche regulates immunity through three interconnected dimensions: angiocrine education, whereby vascular- and stromal-derived signals reprogram myeloid and lymphoid cell states; metabolic exclusion, whereby endothelial metabolic rewiring, lactate accumulation, acidosis, and nutrient competition impair immune-cell fitness and function; and structural barricading, whereby pericyte loss, abnormal vascular branching, and vasculogenic mimicry restrict immune-cell trafficking and infiltration. Rather than acting independently, these mechanisms form a self-reinforcing vascular–immune circuit in which structural abnormalities intensify hypoxic and metabolic stress, metabolic perturbations reshape endothelial and stromal signaling, and angiocrine programs further reinforce immunosuppressive immune states and vascular dysfunction. We further discuss how this framework manifests across spatially specialized perivascular, hypoxic, venular, stem cell-associated, and pre-metastatic niches, generating substantial heterogeneity within and across tumor types. From a translational perspective, this integrated framework provides a basis for defining tumor vascular niche states that may inform biomarker development, patient stratification, and the rational selection of vascular normalization, metabolic intervention, and vascular–immune combination therapies. By conceptualizing the tumor vascular niche as a spatially organized and mechanistically integrated immune-regulatory system, this review provides a framework for linking vascular pathology to immune dysfunction and for guiding mechanism-informed precision oncology.