Characterization of KLK5-high epithelial cells and their interactions with the tumor microenvironment in high-grade serous ovarian cancer

Abstract Ovarian cancer remains a significant global health burden, with high-grade serous ovarian cancer (HGSOC) representing the most lethal subtype. Bulk RNA-seq analysis revealed KLK5 (Kallikrein-5, a serine protease) upregulation in ovarian cancer, correlating with shortened disease-free survival (DFS) and advanced stage in TCGA cohorts. In vitro functional assays further demonstrated that KLK5 promotes metastatic potential in ovarian cancer cells, indicating its role in disease progression. Single-cell and spatial transcriptomic analysis identified elevated KLK5 expression specifically in HGSOC epithelial cells. Concurrently, KLK5-high tumors exhibited enrichment of collagen-related genes (COL1A1/2, COL6A2) within the fibroblast compartment, suggesting KLK5-driven epithelial-stromal crosstalk mediated by collagen signaling. The co-expression of KLK5 with AGRN implicated extracellular matrix (ECM) remodeling as a potential progression mechanism. Immune profiling revealed that KLK5-high tumor microenvironments (TMEs) harbor increased populations of immunosuppressive myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Enhanced CD8 + T cell-macrophage interactions observed in these KLK5-high tumors may drive macrophage reprogramming and contribute to immune evasion. In conclusion, KLK5 promotes HGSOC progression through stromal activation, AGRN-mediated ECM alterations, and the reshaping of the TME towards an immunosuppressive state. KLK5’s dual role as both a prognostic biomarker and a potential therapeutic target positions it as a promising candidate for precision oncology in HGSOC.