Single-cell transcriptomics reveals a correlation between inflammatory C7 fibroblasts in cervical tumor-adjacent normal tissues and cervical cancer progression.

INTRODUCTION: Cervical cancer is a common gynecological malignancy, having high incidence and mortality rates, especially in developing regions. The tumor microenvironment (TME) plays a crucial role in disease progression, and cancer-associated fibroblasts (CAFs) are key components of the TME. However, the roles of CAFs in tumor-adjacent normal tissue remain unclear. METHODS: Herein, we used single-cell RNA sequencing to generate high-resolution cellular atlases of cervical cancer and tumor-adjacent normal tissue, systematically profiling fibroblast-cancer cell interactions and comparing fibroblasts from distinct origins. Pseudotime analysis and CytoTRACE scoring were employed to investigate the developmental trajectory of fibroblasts. Immunohistochemistry validated the inflammatory CAF (iCAF) subpopulation of C7 fibroblasts and assessed its correlations with clinicopathological features. RESULTS: We found that C7 fibroblasts secrete CXCL12 to activate the ACKR3 (CXCR7) receptor in cancer cells, thereby promoting tumor cell proliferation, invasion, and metastasis. C7 fibroblasts also highly expressed multiple oncogenic genes, including IL6, CXCL3, CXCL2, CCL2, GPC3, PLAU, TNFAIP6, PTX3, and EIF4A3, and genes associated with poor prognosis, including CXCL3, TNFAIP6, PTX3, IGSF10, and LDLR. High C7 fibroblast abundance was associated with advanced International Federation of Gynecology and Obstetrics stage, lymph node metastasis, and postmenopausal status. DISCUSSION: Our findings suggest that C7 fibroblasts being predominantly distributed in tumor-adjacent normal tissues is significantly associated with cervical cancer progression, and that C7 fibroblasts in these tissues may serve as potential biomarkers and therapeutic targets for tumor microenvironment modulation.