Tumor-associated high endothelial venules as therapeutic modulation targets in cancer immunotherapy

Immunotherapy has shown remarkable efficacy in improving the prognosis and survival rates of cancer patients, yet the overall response rate remains relatively low. The discovery of high endothelial venules (HEVs) and tertiary lymphoid structures (TLSs) has brought new hope to antitumor immunity. HEVs, as specialized vascular structures, facilitate lymphocyte infiltration and enhance tumor immune responses, while TLSs provide an organized immune microenvironment that further supports antitumor immunity. Current studies often emphasize the immunoregulatory roles of HEVs or TLSs from relatively independent perspectives, overlooking the fact that the two constitute a temporospatially interactive and unified system. This review systematically explores the interdependence and interactions between tumor-associated high endothelial venules (TA-HEVs) and TLSs in terms of their development, organization, and function. From an integrative perspective, it highlights current pharmacological strategies aimed at inducing intratumoral HEVs and TLSs to enhance the efficacy of immunotherapy. Finally, the review discusses future perspectives on the potential molecular mechanisms underlying HEV formation, methodologies for HEV detection, and the development of precision-targeted therapies to modulate HEV/TLS formation.