Microenvironmental heterogeneity and molecular features associated with lymphovascular invasion in pancreatic ductal adenocarcinoma

Lymphovascular invasion, a histopathological hallmark of aggressive pancreatic ductal adenocarcinoma (PDAC) characterized by tumor cells within vascular channels, significantly correlates with poor patient outcomes, yet its molecular consequences remain incompletely understood. Our integrated multi-omics approach combining single-cell RNA sequencing of 24 PDAC specimens with functional validation reveals that lymphovascular invasion-positive tumors exhibit i) a profoundly immunosuppressive tumor microenvironment marked by dysfunctional CD8 + T cells and M2-polarized macrophages, ii) an activated stromal signature with prominent cancer-associated fibroblast activity, and iii) tumor cell-intrinsic up-regulation of bone marrow stromal cell antigen 2 (BST2), a novel prognostic biomarker functionally implicated in enhanced metastatic potential through a sequential signaling axis—BST2 activates IL-6/STAT3 signaling, which in turn up-regulates TGF-β1 to drive epithelial–mesenchymal transition. Through orthogonal validation using in vitro invasion assays and in vivo models, we demonstrate that BST2 not only serves as a clinical predictor of aggressive disease but is also functionally implicated in and represents a potential therapeutic target for PDAC's invasive phenotype. These findings provide a comprehensive characterization of lymphovascular invasion-associated molecular alterations and establish a precision medicine framework for targeting this high-risk PDAC subset.