Researchers at Columbia University and the University of Toronto have identified a previously unknown subgroup of cancer-associated fibroblasts that helps lung tumours evade immune attack. The cells, described as immunomodulatory cancer-associated fibroblasts, or imCAFs, are distinguished by expression of CHL1, a gene not normally found in fibroblasts in healthy lungs. They produce the signalling protein CXCL9, which attracts highly suppressive CXCR3-positive regulatory T cells to the edge of the tumour. Regulatory T cells normally prevent excessive inflammation in the lungs, but inside the tumour environment their function is effectively hijacked: they suppress anti-cancer immunity and create a protective zone around malignant cells.
In mouse models, researchers disrupted this pathway either by removing CXCR3 from regulatory T cells or CXCL9 from stromal cells. Fewer suppressive T cells accumulated around the tumours, cancer-killing CD8+ T cells became more active and overall tumour burden fell. The team also identified similar CHL1-positive fibroblasts in human non-small cell lung cancer samples. Patients whose tumours contained more of these cells showed weaker anti-tumour immune activity and shorter progression-free survival. The CHL1–CXCL9–CXCR3 pathway therefore represents a potential therapeutic target, although the work does not yet show that blocking it will be safe or effective in patients. The intervention has so far been demonstrated experimentally, primarily in mice.
The potential significance is considerable. WHO and IARC estimates indicate that around 2.5 million people were diagnosed with lung cancer worldwide in 2022 and more than 1.8 million died from the disease, making it the leading cause of cancer death globally. Non-small cell lung cancer accounts for roughly 85% of cases. The study, published in Nature Immunology on August 11, 2026, does not provide a new treatment yet, but reveals another way in which tumours can turn the body’s normal immune-regulating machinery to their advantage – and potentially exposes a new weakness for future immunotherapies to exploit.
Sources: Nature Immunology, Columbia University Irving Medical Center, WHO, IARC.
