S100A4 characterize antigen-presenting cancer-associated fibroblasts and predicts surgical outcomes in relapsed ovarian cancer

Background: Relapsed ovarian cancer (ROC) presents significant therapeutic challenges, and complete resection during secondary cytoreductive surgery (SCR) has been associated with improved survival. However, the contribution of the tumor microenvironment (TME), particularly cancer-associated fibroblasts (CAFs), to surgical outcomes remains unclear. Objectives: This study aimed to characterize CAFs heterogeneity in ROC and identify specific CAF subsets associated with immune modulation and surgical prognosis. Design: A multi-platform integrative study combining spatial, single-cell, and transcriptomic analyses to investigate CAF phenotypes and their clinical relevance in ROC. Methods: Multiplex immunohistochemistry and spatial digital phenotyping were performed on 31 ROC samples. Single-cell RNA sequencing (scRNA-seq) was conducted on 11 tumors to define CAF clusters. Transcriptomic meta-analysis across multiple external datasets was used to evaluate prognostic significance. Spatial relationships between CAF subsets and immune cells were analyzed, and antigen-presenting CAF signatures were assessed based on marker co-expression patterns. Results: apCAFs-related genes correlated with improved overall survival (hazard ratio = 0.81, 95% confidence interval: 0.69-0.95). Conclusion: apCAFs as potential prognostic biomarkers and immunomodulatory targets, offering new perspectives for personalized therapeutic strategies in ROC.