Spatiotemporal analyses of the pan-cancer single-cell landscape reveal widespread profibrotic ecotypes regulating tumor immunity

Abstract: The tumor microenvironment (TME) evolves during tumor development and influences the immune and stromal cells to orchestrate a supportive environment for tumor growth. The composition and functional state of the TME can vary considerably among different organs due to the presence of tissue-resident cells. Here, we collected 4,483,367 cells from 746 donors across 36 cancer types, including normal, precancerous, primary, and metastatic tumors, and constructed a pan-cancer resource named TabulaTIME. Our integrated analyses reveal that CTHRC1 is a hallmark of extracellular matrix-related cancer-associated fibroblasts (CAFs) that are prevalent enriched in different cancer types. Spatiotemporal analyses further indicated that CTHRC1⁺ CAFs are located at the leading edge between the malignant and normal regions, potentially preventing immune infiltration. Moreover, we identified a profibrotic macrophage subtype marked by SLPI expression that is also involved in extracellular matrix remodeling and colocalized with CTHRC1⁺ CAFs to form unique spatial ecotypes. Finally, we demonstrated that TabulaTIME can be utilized to analyze tumor ecotype composition in large-scale cohorts and serve as a reference for cell type annotation. This work establishes a comprehensive single-cell landscape of the heterogenous TME, encompassing both immune and stromal cells, and offers a potential therapeutic strategy for targeting the profibrotic ecotype in cancer treatment.