A CAF-Associated Stromal Remodeling Signature Links Immune Exclusion to Exhaustion-Prone CD8+ T-Cell Dysfunction in High-Grade Serous Ovarian Cancer.

High-grade serous ovarian carcinoma (HGSOC) shows limited benefit from immune checkpoint blockade, partly because stromal barriers impair antitumor immunity. We developed a cancer-associated fibroblast (CAF)-associated mitochondrial metabolic and matrix-remodeling signature, termed CMMS, to characterize this immune-suppressive stromal state. CMMS integrated contractile/myCAF, extracellular matrix (ECM), and mitochondrial metabolic genes. Its clinical, metabolic, and immune relevance was evaluated in TCGA-HGSOC, independent GEO cohorts, single-cell RNA-seq datasets, and an anti-PD-L1-treated cohort, followed by cell-cell communication and experimental validation. LASSO-weighted CMMS stratified overall survival, with high CMMS indicating poorer prognosis. CMMS-high tumors exhibited ECM/TGFβ activation; associations with COL1A1, POSTN, and LOX; and a hypoxia-dominant metabolic phenotype. Mediation analysis suggested that hypoxia largely linked CMMS to glycolytic remodeling. Immune profiling revealed stromal-rich immune exclusion, checkpoint activation, and exhaustion-prone T-cell dysfunction. Single-cell analysis localized CMMS mainly to myCAF-like ECM-remodeling CAFs. In validation datasets, CMMS-high CAFs were associated with reduced CD8 abundance, increased CD8 exhaustion, and stronger matrix- and chemokine-related communication with T cells. Experiments further supported a link between TGFβ-related fibroblast activation, ECM-remodeling features, and impaired CD8+ T-cell effector function. Overall, CMMS defines a CAF-enriched fibrotic-hypoxic stromal program associated with immune exclusion-related features, exhaustion-prone T-cell dysfunction, and poor outcome in HGSOC.