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.