A novel CAF population coordinates hyper-suppressive regulatory T cell recruitment and localization in lung cancer

Abstract Across many solid tumor types, cancer-associated fibroblasts (CAFs) are abundant and heterogeneous, with distinct subpopulations exerting immunomodulatory functions. Here we identify a novel population of immunomodulatory CAFs (imCAFs) in primary lung adenocarcinoma and pulmonary metastases, characterized by cell adhesion molecule L1-like (CHL1) expression and enriched in immune regulation and chemokine signaling programs. Through single-cell and spatial transcriptomics, we demonstrate that imCAFs are spatially colocalized with CXCR3 + regulatory T (T reg ) cells, a hyper-suppressive subset accumulating at the tumor border. imCAFs produce CXCL9, driving CXCR3 + T reg cell recruitment and promoting an immunosuppressive microenvironment. CXCR3 + T reg cells display enhanced proliferative and suppressive capacity and are transcriptionally distinct from CXCR3 − counterparts. Genetic ablation of Cxcr3 in T reg cells or Cxcl9 in stromal cells reduces T reg cell accumulation, enhances CD8 + T cell activation and decreases tumor burden. Analogous CHL1 + imCAF-like fibroblasts in human non-small cell lung cancer colocalize with T reg cells, and elevated CHL1 expression is associated with reduced cytotoxicity and decreased progression-free survival, highlighting the imCAF–CXCL9–CXCR3 + T reg axis as a promising therapeutic target.