<p>Ascites, a hallmark of advanced ovarian cancer, severely impairs patient quality of life and contributes to therapeutic resistance. Current management strategies remain primarily palliative, highlighting the urgent need to elucidate the underlying mechanisms. Although TREM2⁺ macrophages are enriched in malignant ascites, the role of soluble TREM2 (sTREM2) in regulating vascular function and ascites pathogenesis remains poorly understood. Here, we show that sTREM2 levels are elevated in malignant ascites and positively correlate with ascites volume. Using a combination of in vitro, in vivo, and ex vivo models, we demonstrate that sTREM2 promotes vascular permeability and drives ascites formation. Mechanistically, sTREM2 binds to nucleolin (NCL) on endothelial cells and activates the AKT/eNOS signaling pathway, which leads to VE-cadherin phosphorylation and ultimately vascular leakage. sTREM2-induced hyperpermeability was abolished by NCL knockdown or eNOS inhibition. Importantly, administration of a neutralizing antibody against sTREM2 significantly reduced ascites formation and tumor burden in mouse models. Our study identifies the sTREM2-NCL-AKT-eNOS axis as a critical driver of vascular leakage and malignant ascites in ovarian cancer, highlighting it as a promising therapeutic target.</p>