A newly identified population of fibroblasts may play a key role in helping lung tumours suppress the body’s immune response, according to a study published in Nature Immunology. The findings provide new insight into how the tumour microenvironment can actively support cancer progression and point towards potential strategies for improving anti-cancer immunotherapy.
Lung cancer remains one of the most lethal forms of cancer and is the leading cause of cancer-related death in the United States. Although immunotherapy has transformed the treatment of several cancers, including lung cancer, many tumours remain resistant to immune-mediated destruction. Increasing evidence suggests that this resistance may not depend solely on the cancer cells themselves but also on the complex network of immune and non-immune cells surrounding the tumour.
The new study focused on fibroblasts, connective tissue cells that are commonly found within and around solid tumours. Once considered primarily structural cells, fibroblasts are now increasingly recognised as active participants in cancer development. They can influence tumour growth, tissue remodelling, blood vessel formation and immune activity within the tumour microenvironment.
Using single-cell transcriptomic profiling in a mouse model of lung cancer, the researchers examined the diversity of fibroblasts associated with tumour development. Their analysis identified a previously unrecognised population of fibroblasts characterised by expression of the CHL1 gene. CHL1 is not normally expressed by fibroblasts in healthy lung tissue, suggesting that these cells may represent a specialised population that emerges during tumour development.
Further experiments showed that these CHL1-positive fibroblasts contribute to the creation of an immunosuppressive environment around lung tumours. The cells were found to recruit regulatory T cells, or Tregs, to the tumour border, where they can dampen the immune response against cancer. Tregs normally play an essential role in protecting tissues from excessive immune activation. This function is particularly important in the lungs, which are constantly exposed to environmental particles, microorganisms and other antigens. However, tumours can exploit these immune-regulating mechanisms to protect themselves from immune attack.
The researchers found that CHL1-positive fibroblasts recruit Tregs through the signalling protein CXCL9. The resulting accumulation of these immunosuppressive cells around the tumour appears to weaken the body’s anti-tumour immune response, creating conditions that allow cancer cells to survive and continue growing.
In experiments involving mice, disruption of the pathway responsible for Treg recruitment reduced the accumulation of these cells near the tumour and was associated with a stronger anti-tumour immune response. The findings suggest that interfering with communication between tumour-associated fibroblasts and immune cells could help restore immune activity against cancer.
The researchers also identified similar CHL1-positive fibroblasts in human lung cancer samples. Analysis of tumour specimens and clinical data indicated that higher levels of these fibroblasts were associated with weaker anti-tumour immune responses and shorter progression-free survival. Although these findings do not establish that the cells directly cause poorer clinical outcomes, they suggest that their presence may have important biological and potentially prognostic significance.
The discovery adds to growing evidence that the tumour microenvironment plays an active role in determining whether the immune system can effectively recognise and eliminate cancer cells. While current immunotherapies largely focus on activating immune cells or blocking inhibitory signals that restrain them, targeting other components of the tumour environment could provide an additional approach. The study highlights two potential therapeutic strategies. One approach would be to prevent the development or accumulation of CHL1-positive fibroblasts within tumours. Another would be to block the signals, including the CXCL9-mediated pathway, through which these cells recruit immunosuppressive Tregs.
The apparent absence of CHL1-positive fibroblasts from healthy lung tissue could make them particularly attractive therapeutic targets. A treatment capable of selectively disrupting these tumour-associated cells might reduce local immune suppression while limiting unwanted effects on normal lung tissue. However, further research will be needed to understand how these fibroblasts arise, whether they perform additional functions within tumours and whether targeting them can be achieved safely in patients.
The researchers emphasise that the findings remain at an early stage and that additional preclinical and clinical studies will be required before the approach can be translated into a treatment. Nevertheless, the study provides an important new perspective on the mechanisms through which lung tumours manipulate their surrounding environment.
By revealing how a specialised population of fibroblasts can recruit immune-suppressing cells and create a protective niche around tumours, the research suggests that the next generation of cancer immunotherapies may need to look beyond cancer cells and immune cells alone. Targeting the cellular interactions within the tumour microenvironment could offer a new avenue for overcoming immune resistance and improving the effectiveness of treatment for lung cancer.
References
- Ringham OR, Rivera M, Loffredo LF, Ozsoy MA, Healy CM, Cheng MF, et al. A novel CAF population coordinates hyper-suppressive regulatory T cell recruitment and localization in lung cancer. Nat Immunol. 2026. doi:10.1038/s41590-026-02607-2.