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

Though they have been well characterized in malignancies considered to be highly desmoplastic, how distinct CAF populations in lung adenocarcinoma (LUAD) influence the tumor–immune microenvironment is not well understood. Here, we identify a novel population of immunomodulatory CAFs (imCAFs) in the LUAD tumor microenvironment, characterized by CHL1 expression and enriched in transcriptional programs involving immune regulation and chemokine signaling.

Through single-cell and spatial transcriptomics, we demonstrate that imCAFs are spatially colocalized with CXCR3+ regulatory T (Treg) cells, a hyper-suppressive T cell subset that accumulates at the tumor border. Mechanistically, imCAFs produce CXCL9, a key chemoattractant that mediates the recruitment of CXCR3+ Tregs to the tumor, promoting an immunosuppressive microenvironment. Functional profiling reveals that tumor-resident CXCR3+ Tregs possess enhanced proliferative and suppressive capacity and are transcriptionally distinct from CXCR3- counterparts.