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

The tumor microenvironment evolves during tumor development and influences the cells in the microenvironment to orchestrate a supportive environment for tumor growth. Here we collected 4,483,367 cells across 36 cancer types 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 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 that SLPI⁺ macrophages exhibit profibrotic-associated phenotypes and colocalize with CTHRC1⁺ CAFs to form unique spatial ecotypes. Finally, we demonstrated that TabulaTIME can be used to analyze tumor ecotype composition and can serve as a reference for cell-type annotation. This work establishes a comprehensive single-cell landscape of the heterogenous TME and offers a potential therapeutic strategy for targeting the profibrotic ecotype in cancer treatment.