Single-cell and spatial transcriptomics reveal TNC-positive cancer-associated fibroblasts that mediate immunosuppression and promote tumor progression in basal cell carcinoma.

BACKGROUND: The global incidence of basal cell carcinoma (BCC) is steadily increasing. Although immunotherapy has emerged as a treatment option, its efficacy remains limited. This underscores the need for further investigation of immune remodeling mechanisms in BCC. Here, we aimed to characterize fibroblast subsets and their interactions with other components of the tumor microenvironment in BCC. METHODS: We performed single-cell RNA sequencing on nine surgical specimens from six patients, including BCC tumors and adjacent normal tissues. Key findings were further validated using spatial transcriptomics and multiplex immunohistochemistry. RESULTS: We identified the C01_TNC fibroblast cluster as a population of cancer-associated fibroblasts (CAFs). These cells exhibited prominent peritumoral infiltration and were characterized by matrix-associated and inflammatory gene expression profiles. We propose that C01_TNC CAFs contribute to tumor progression, possibly by upregulating collagens that engage integrins on tumor cells, thereby facilitating extracellular matrix remodeling and invasion. Furthermore, C01_TNC CAFs were spatially associated with Tregs and expressed ligands that interact with Treg receptors, suggesting a role in enhancing immunosuppression. Notably, this subset was significantly enriched in peritumoral regions and could establish an immune barrier favoring tumor progression. CONCLUSIONS: Our findings shed light on the role of fibroblasts in orchestrating interactions between tumor and immune cells in BCC. This enhanced understanding of the tumor microenvironment may inform novel therapeutic strategies to improve treatment outcomes for patients with BCC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-025-07491-2.