The role and mechanisms of ESM1 in tumors

Endothelial cell-specific molecule-1 (ESM1, also known as endocan), is a sulfated proteoglycan primarily secreted by vascular endothelial cells, although it can also be expressed by tumor cells and stromal cells. Since its overexpression in multiple tumors was systematically confirmed in 2006, ESM1 has become a research hotspot as a tumor biomarker and therapeutic target. This review systematically elaborates on the role of ESM1 in tumors at three levels. First, we analyze the multilayered regulatory mechanisms underlying its upregulation, including transcription factor activation, growth factor and inflammatory signaling, epigenetic modifications, and non-coding RNA regulation, as well as induction by the metabolic microenvironment and pathogen infection. Second, we clarify the dual biological functions of ESM1. In most tumors, ESM1 drives malignant progression through five major dimensions: angiogenesis, malignant behavior and epithelial–mesenchymal transition, metabolic reprogramming, therapeutic resistance, and immune remodeling. Limited evidence suggests that ESM1 may exert antitumor effects in specific contexts, such as prostate cancer, gastric cancer, colon cancer, and non-glycosylated forms of ESM1; however, such evidence is far less abundant than that supporting its pro-tumorigenic role, and its determinants: tumor type, cell source, glycosylation status, disease stage, and experimental model remain unclear. Finally, we evaluate its clinical translational value. As a diagnostic biomarker and prognostic indicator, ESM1 can be detected in various body fluids and is associated with tumor invasion, metastasis, and survival. However, current diagnostic and prognostic evidence is largely retrospective, single-center, and based on non-standardized detection methods. Circulating ESM1 is also confounded by infection, inflammation, tissue damage and bone marrow regeneration, and its cross-cancer diagnostic value has not yet been confirmed. As a therapeutic target, anti-ESM1 strategies show promising prospects for reversing drug resistance and combination therapy, but prospective clinical validation, safety assessment, and evidence for the feasibility of tumor-selective targeting are still lacking. In addition, ESM1 of endothelial origin and ESM1 of tumor or stromal origin may differ in functional interpretation and biomarker interpretation, yet most existing studies have not rigorously distinguished between these sources. In summary, ESM1 is a key molecular node integrating tumor angiogenesis, immune evasion, and therapeutic resistance, and its clinical translational potential as a circulating biomarker and targeted therapy warrants further exploration.