Endothelial cells (ECs) in the tumor microenvironment play a critical role in tumor angiogenesis, immune regulation, and cancer progression. Tumor-associated ECs differ from normal ECs in phenotype, gene expression, and function, exhibiting high proliferative potential and the ability to activate immunosuppressive mechanisms that support tumor growth and metastasis. These cells can trans-differentiate into mesenchymal cells through endothelial-to-mesenchymal transition (EndMT), contributing to tumor progression and resistance to chemotherapy. Tumor-associated ECs also act as gatekeepers for immune cells, influencing antitumor immunity by priming, activating, or downregulating effector immune cells. They are involved in the formation of tertiary lymphoid structures (TLS), which enhance immune responses to immune checkpoint inhibitors (ICI). Tumor-associated ECs are characterized by irregular morphology, increased vascular permeability, and abnormal gene expression profiles, including upregulation of stem cell markers and downregulation of von Willebrand factor. These cells are also involved in the regulation of immune cell trafficking, including Treg cell infiltration and effector T cell suppression. Tumor-associated ECs can express immune checkpoint ligands such as PD-L1, which inhibit T cell function. They also contribute to the development of immunosuppressive environments by expressing IDO, which promotes T cell apoptosis and Treg cell activation. Tumor-associated ECs can act as semi-professional antigen-presenting cells, activating memory T cells and Treg cells. The interaction between Treg cells and ECs via ICOS/ICOSL enhances Bcl-2 expression on ECs, improving the sensitivity of B-lymphoma cells to Bcl-2 inhibitors. Tumor-associated ECs are also involved in the formation of TLS, which can have pro- or anti-tumor effects depending on their composition and location. TLS are associated with improved immune responses and better prognosis in certain cancers. Tumor-associated ECs are also involved in the regulation of lymphatic vessels through VEGFC/VEGFR3 signaling, which promotes lymphangiogenesis and metastasis. The FDA has approved several drugs targeting VEGFC/VEGFR3, including sorafenib, sunitinib, pazopanib, and axitinib, for the treatment of various cancers. The combination of anti-angiogenic therapies with immunotherapy strategies, including ICI, CAR T cells, and bispecific antibodies, aims to impact both ECs and immune cells to block angiogenesis and enhance antitumor immune responses. Understanding the complex role of tumor-associated ECs in the tumor microenvironment is crucial for developing targeted therapies to improve cancer treatment.Endothelial cells (ECs) in the tumor microenvironment play a critical role in tumor angiogenesis, immune regulation, and cancer progression. Tumor-associated ECs differ from normal ECs in phenotype, gene expression, and function, exhibiting high proliferative potential and the ability to activate immunosuppressive mechanisms that support tumor growth and metastasis. These cells can trans-differentiate into mesenchymal cells through endothelial-to-mesenchymal transition (EndMT), contributing to tumor progression and resistance to chemotherapy. Tumor-associated ECs also act as gatekeepers for immune cells, influencing antitumor immunity by priming, activating, or downregulating effector immune cells. They are involved in the formation of tertiary lymphoid structures (TLS), which enhance immune responses to immune checkpoint inhibitors (ICI). Tumor-associated ECs are characterized by irregular morphology, increased vascular permeability, and abnormal gene expression profiles, including upregulation of stem cell markers and downregulation of von Willebrand factor. These cells are also involved in the regulation of immune cell trafficking, including Treg cell infiltration and effector T cell suppression. Tumor-associated ECs can express immune checkpoint ligands such as PD-L1, which inhibit T cell function. They also contribute to the development of immunosuppressive environments by expressing IDO, which promotes T cell apoptosis and Treg cell activation. Tumor-associated ECs can act as semi-professional antigen-presenting cells, activating memory T cells and Treg cells. The interaction between Treg cells and ECs via ICOS/ICOSL enhances Bcl-2 expression on ECs, improving the sensitivity of B-lymphoma cells to Bcl-2 inhibitors. Tumor-associated ECs are also involved in the formation of TLS, which can have pro- or anti-tumor effects depending on their composition and location. TLS are associated with improved immune responses and better prognosis in certain cancers. Tumor-associated ECs are also involved in the regulation of lymphatic vessels through VEGFC/VEGFR3 signaling, which promotes lymphangiogenesis and metastasis. The FDA has approved several drugs targeting VEGFC/VEGFR3, including sorafenib, sunitinib, pazopanib, and axitinib, for the treatment of various cancers. The combination of anti-angiogenic therapies with immunotherapy strategies, including ICI, CAR T cells, and bispecific antibodies, aims to impact both ECs and immune cells to block angiogenesis and enhance antitumor immune responses. Understanding the complex role of tumor-associated ECs in the tumor microenvironment is crucial for developing targeted therapies to improve cancer treatment.