Endothelial plasticity as a continuum in the tumor microenvironment.

Abstract

The tumor microenvironment (TME) is a dynamic and complex ecosystem, in which endothelial cells (ECs) play a central role beyond their traditional function as passive vascular conduits. Increasing evidence indicates that tumor-associated endothelial cells (TECs) undergo profound phenotypic and functional reprogramming, acquiring plasticity that enables them to adapt to hypoxic, inflammatory, and metabolic stresses. This plasticity encompasses a spectrum of states, including angiogenic activation, immune modulation, metabolic reprogramming, and endothelial-to-mesenchymal transition (EndMT). These transitions contribute to abnormal tumor vasculature, immune evasion, and therapeutic resistance. Advances in single-cell transcriptomics, spatial biology, and molecular pathology have revealed distinct endothelial subpopulations with unique biomarker signatures and functional roles within tumors. Importantly, TEC plasticity is now recognized as a key determinant of response to anti-angiogenic therapies and immune checkpoint inhibitors. This review synthesizes current knowledge on endothelial plasticity in cancer, proposes a conceptual framework for classifying TEC phenotypes, and highlights emerging biomarkers and therapeutic strategies targeting endothelial reprogramming. Understanding the dynamic nature of endothelial cells within the TME may enable the development of precision vascular therapies aimed at normalizing tumor vasculature and improving clinical outcomes.