A GROUNDBREAKING study has unveiled the dual nature of Cancer-associated Fibroblasts (CAFs) in regulating anti-tumour immunity, providing new insights into their complex roles in cancer progression. CAFs, which play a key role in shaping the tumour microenvironment, can either promote or hinder the immune response. This research, published recently, utilised single-cell and spatial transcriptomic analyses to investigate these fibroblasts in head and neck squamous cell carcinoma (HNSCC), classifying the tumours into immune-hot (HPV-positive) and immune-cold (HPV-negative) subgroups.
The study identified six distinct CAF subpopulations, two of which exhibited immunomodulatory gene expression profiles. One group, termed IL-11+ inflammatory CAF (iCAF), was linked to inflammatory monocytes and activated through NF-κB signalling, which is triggered by cytokines such as IL-1β and TNF-α. The second group, the CCL19+ fibroblastic reticular cell (FRC)-like CAFs, was predominantly found in immune-hot HPV-positive tumours, where it was associated with CD4+ T-cells and B-cells in tertiary lymphoid structures and regulated through lymphotoxin-driven non-canonical NF-κB signalling.
Further analysis revealed that iCAFs were also present in gastrointestinal cancers, distinct from those in pancreatic and breast cancers. Interestingly, FRC-like fibroblasts, which are linked to better survival outcomes, were found in low frequencies across various tumour types and associated with enhanced response to checkpoint immunotherapy.
This research clarifies the immune-modulatory roles of CAFs, particularly in shaping immune microenvironments, offering potential avenues for therapeutic strategies targeting CAFs to improve cancer treatment outcomes. The study underscores the importance of these fibroblasts in both promoting and suppressing anti-tumour immunity across different cancer types.
Helena Bradbury, EMJ
Reference
Jenkins BH et al. Single cell and spatial analysis of immune-hot and immune-cold tumours identifies fibroblast subtypes associated with distinct immunological niches and positive immunotherapy response. Mol Cancer. 2025;24(1):3.
