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Researchers have identified a previously unknown population of cancer-associated fibroblasts (CAFs) that appears to play a crucial role in helping lung tumors escape the body’s immune defenses. The study, published in Nature Immunology, introduces these cells as immunomodulatory cancer-associated fibroblasts (imCAFs) and suggests they actively organize an immune-suppressive environment around lung tumors.
Cancer-associated fibroblasts are support cells found within the tumor microenvironment. While they do not become cancer cells themselves, they can influence how tumors grow, spread, and interact with the immune system. This research demonstrates that a specific subtype of these fibroblasts expresses CHL1, a cell adhesion molecule that distinguishes them from other fibroblast populations.
Using single-cell RNA sequencing, spatial transcriptomics, and advanced imaging techniques, researchers discovered that CHL1-positive imCAFs produce the signaling molecule CXCL9, which attracts a specialized group of CXCR3-positive regulatory T cells (Tregs) to the edges of lung tumors. These regulatory T cells suppress immune responses, preventing cytotoxic T cells from effectively attacking cancer cells.
The study found that these recruited regulatory T cells are highly suppressive and accumulate around tumor borders, creating an environment that protects cancer from immune attack. In mouse models, removing CXCL9 from stromal cells or disabling CXCR3 in regulatory T cells significantly reduced Treg accumulation, enhanced CD8+ T-cell activity, and lowered tumor burden.
Researchers also identified similar CHL1-positive imCAF-like fibroblasts in human non-small cell lung cancer samples. Patients with higher CHL1 expression showed reduced anti-tumor immune activity and poorer progression-free survival, suggesting this fibroblast population may serve as both a prognostic biomarker and a potential therapeutic target.
The findings reshape current understanding of the tumor microenvironment by showing that fibroblasts are not merely structural support cells but active regulators of immune suppression. Targeting the imCAF–CXCL9–CXCR3 signaling pathway could improve the effectiveness of existing immunotherapies, including immune checkpoint inhibitors, while potentially avoiding the risks associated with eliminating all regulatory T cells. However, the research remains preclinical, and additional studies and clinical trials will be required before this strategy can be translated into routine patient care.