Spatial Atlas of Upper Tract Urothelial Carcinoma Identifies SLC14A1+ and S100A8/9+ Tumor Cells as Key Determinants of Malignant Progression.

Upper tract urothelial carcinoma (UTUC) is characterized by a high incidence of muscle invasion and distinct molecular heterogeneity, with tumor microenvironment (TME) heterogeneity playing a pivotal role in its malignant progression. However, the spatial distribution patterns of functional cell populations in UTUC and their regulatory mechanisms driving high-grade (HG) and muscle-invasive (MI) progression remain largely unelucidated. Herein, we integrated single-cell RNA sequencing (scRNA-seq) and spatial transcriptome sequencing (ST-seq) to systematically characterize the cellular landscape, spatial molecular network, and intercellular communication profile of UTUC tissues. Six tumor cell subpopulations were identified in UTUC, among which SLC14A1⁺ tumor cells were correlated with favorable clinical prognosis, whereas S100A8/9⁺ tumor cells were associated with poor clinical outcomes. Mechanistically, SLC14A1⁺ tumor cells decelerated UTUC progression via modulating cell apoptosis mediated by the FASLG-TNFRSF10B ligand-receptor pair. In contrast, S100A8/9⁺ tumor cells promoted the malignant progression of UTUC by regulating extracellular matrix remodeling and epithelial-mesenchymal transition (EMT) via the CCL19-CCR7, CCN2-EGFR, ADAM28-ITGA4 and CD14-ITGB2 ligand-receptor pairs. Collectively, our study uncovers the cellular and spatial heterogeneity of the UTUC TME, identifies SLC14A1⁺ tumor cells as a tumor-suppressive subpopulation and S100A8/9⁺ tumor cells as a key driver of UTUC malignant progression, and further delineates the core spatial signaling pathways underlying HG and MI progression of UTUC. These findings provide novel prognostic biomarkers and potential therapeutic targets for UTUC, and advance our mechanistic understanding of spatial TME regulation in urothelial carcinoma.