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: We identified a predominant S100A4 + CAFs population enriched in the tumor-adjacent stroma, characterized by extracellular matrix remodeling and immune-regulatory gene expression. S100A4 + CAFs displayed closer spatial proximity to T cells and were significantly associated with complete tumor resection (R0) outcomes. Furthermore, a distinct antigen-presenting subset co-expressing CD74 (S100A4 + apCAFs) exhibited enhanced interaction with CD4 + T cells and was significantly enriched in R0 patients. Meta-analysis across multiple transcriptomic datasets revealed that high expression of S100A4 + apCAFs-related genes correlated with improved overall survival (hazard ratio = 0.81, 95% confidence interval: 0.69–0.95). Conclusion: This study identifies S100A4 + CAFs—particularly the antigen-presenting S100A4 + apCAF subset—as key components of the ROC microenvironment linked to favorable immune contexture and surgical outcomes. These findings highlight S100A4 + apCAFs as potential prognostic biomarkers and immunomodulatory targets, offering new perspectives for personalized therapeutic strategies in ROC.
Maimaiti et al. (Wed,) studied this question.