Abstract: Objective Bladder cancer is a heterogeneous malignancy with highly metastasis and recurrence rates. Within the tumor microenvironment (TME), cancer⁃associated fibroblasts (CAFs) and extracellular matrix (ECM) remodeling critically influence tumor progression and therapeutic resistance. FK506⁃binding protein 10 (FKBP10) is a molecular chaperone involved in collagen folding and ECM homeostasis, has been implicated in various malignancies. However, its specific role and regulatory mechanisms within the bladder cancer TME remain insufficiently defined. This study aims to investigate the expression profile of FKBP10 in bladder cancer and to systematically elucidate its clinical significance and potential mechanisms in modulating the stromal niche to promote tumor malignancy. Methods Tumor tissue samples were collected from 92 bladder cancer patients who underwent radical cystectomy at The First Affiliated Hospital of Guangxi Medical University between January 2018 and February 2023. Patients were stratified into FKBP10 high⁃ and low⁃expression groups based on FKBP10 transcriptome levels to compare their prognosis and clinical characteristics. Based on Bulk RNA sequencing data, the intergroup heterogeneity were analyzed through differential gene analysis, Gene Set Enrichment Analysis (GSEA), and the xCell algorithm. Differentially upregulated genes in the FKBP10⁃high expression group were extracted and subjected to transcription factor prediction using ChEA3, which integrates ChIP⁃seq data from public repositories such as ENCODE and ReMap, along with RNA⁃seq co⁃expression datasets. Furthermore, the study applied the CellChat algorithm to decipher intercellular communication between FKBP10⁃positive cell subsets and other cell populations. Results In compared to the low⁃expression group (n=69), the high FKBP10 expression group (n=23) exhibited significantly shorter overall survival, along with higher T stage (all P<0.05). In patients with high FKBP10 expression, pathways associated with malignant tumor progression such as extracellular matrix (ECM) remodeling, epithelial⁃mesenchymal transition (EMT), and angiogenesis were significantly activated. PRRX1 and PRRX2 were identified as potential transcription factors regulating these processes. Analysis of the immune microenvironment revealed that the high⁃expression group indicated enrichment of M2 macrophages and elevated expression of immune checkpoint molecules. Single⁃cell RNA sequencing (scRNA⁃seq) analysis revealed that FKBP10 was predominantly expressed in CAFs. Ligand⁃receptor interaction analysis suggested that FKBP10+ CAFs may interact with endothelial cells through the VEGFB/PGF⁃VEGFR1 signaling axis. Conclusions FKBP10 acts as a driver of bladder cancer progression. High FKBP10 expression in bladder cancer is characterized by ECM remodeling and heightened angiogenic activity, which correlates with a poor clinical prognosis. The tumor⁃promoting mechanism likely involves FKBP10+ CAFs facilitating angiogenesis through ECM remodeling and activation of the VEGFB/PGF⁃VEGFR1 signaling axis.

Key words: Bladder cancer, FKBP10, Extracellular matrix, Tumor microenvironment, Cancer?associated fibroblasts