Spatial dynamics of cancer-associated fibroblasts links fibroblastic differentiation to immune exclusion and tumor progression.

INTRODUCTION: Although the role of cancer-associated fibroblasts (CAFs) in cancer progression is increasingly recognized, their spatial dynamics and interactions with immune cells remain poorly understood. METHODS: Here, we present a computational framework that integrates single-cell resolution spatial transcriptomics and standard spatial transcriptomics across multiple tumor types to investigate CAF heterogeneity and its roles in situ. RESULTS: Our analysis presents a continuous transition from fibroblast progenitors to COL11A1-expressing CAFs, which we term aggressive CAFs (aCAFs), within a spatial context. We show that aCAFs, whose expression has been associated with poor prognosis, tend to localize at tumor boundaries, where proximity to tumor cells predicts increased expression of aCAF-associated genes. Spatial modeling shows that regions enriched for COL11A1-expressing CAFs were depleted of non-exhausted immune cells, including naive T cells, activated cytotoxic T cells, and activated B cells, suggesting a role in immune exclusion. Spatial correlation analysis further reveals that aCAFs co-localize with lipid-associated macrophages, a pattern linked to extracellular matrix remodeling and altered lipid metabolism. CONCLUSION: Our study provides insights into the interactions of aCAF, tumor cells, and immune cells in the tumor microenvironment. We also provide an open-source implementation of SpatialAttractor, a toolkit for exploring gene co-expression in the spatial context.