Authors
Olivia R Ringham, Monica Rivera, Lucas F Loffredo, Melih Arda Ozsoy, Christina M Healy, Maye F Cheng, Yinuo Jin, Noah Chen, Kenia de Los Santos-Alexis, Elham Azizi, Anjali Saqi, Matthew B Buechler, Carla P Concepcion-Crisol, Nicholas Arpaia
Published in
Nature immunology. Aug 11, 2026. Epub Aug 11, 2026.
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 (Treg) cells, a hyper-suppressive subset accumulating at the tumor border. imCAFs produce CXCL9, driving CXCR3+ Treg cell recruitment and promoting an immunosuppressive microenvironment. CXCR3+ Treg cells display enhanced proliferative and suppressive capacity and are transcriptionally distinct from CXCR3- counterparts. Genetic ablation of Cxcr3 in Treg cells or Cxcl9 in stromal cells reduces Treg 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 Treg cells, and elevated CHL1 expression is associated with reduced cytotoxicity and decreased progression-free survival, highlighting the imCAF-CXCL9-CXCR3+ Treg axis as a promising therapeutic target.
PMID:
42581185
Bibliographic data and abstract were imported from PubMed on 12 Aug 2026.
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