Genomic instability drives POSTN+ myofibroblasts via STING-WNT axis to promote immunosuppression and PARPi resistance in ovarian cancer
Menée à l'aide de modèles murins et à partir de l'analyse transcriptomique et épigénomique d'échantillons tumoraux prélevés sur des patientes atteintes d'un carcinome séreux ovarien de haut grade, cette étude identifie une sous-population de fibroblastes CAFs similaires aux myofibroblastes et surexprimant POSTN puis met en évidence un mécanisme par lequel l'instabilité génomique favorise l'immunosuppression et la résistance aux inhibiteurs de PARP en induisant le développement de myofibroblastes POSTN+ via la voie de signalisation impliquant les protéines STING et WNT
Cancer-associated fibroblasts (CAFs) are central architects of immunosuppression and therapy resistance across malignancies, yet how tumor-intrinsic genomic instability instructs stromal reprogramming remains unresolved. Integrated single-cell transcriptomics and epigenomics of samples from patients with high-grade serous ovarian carcinoma revealed POSTN+ myofibroblast-like cancer-associated fibroblasts (myCAFs) and effector regulatory T cells (eTreg cells) as critical mediators of immunosuppression in tumors with high genomic instability. Mechanistically, unstable genomes activated tumor-intrinsic STING signaling, triggering WNT3a/7a secretion. WNT/β-catenin signaling in fibroblasts established a POSTN-dependent positive feedback loop that epigenetically locked cells into a POSTN+ myCAF lineage. These myCAFs reciprocally expanded eTreg cells and exhausted CD8+ T cells, thereby converting genomic instability–driven immune activation into suppression and limiting poly(ADP-ribose) polymerase inhibitor (PARPi) efficacy. Therapeutic POSTN blockade reinvigorated T cell cytotoxicity, depleted eTreg cells, and potentiated PARP inhibition in ovarian and breast cancer models, overcoming resistance. Our work resolves the dual roles of genomic instability and identifies POSTN as a stromal-specific checkpoint to mediate immunosuppression in genomically unstable tumors. Epigenetic reprogramming of POSTN+ myCAFs converts genome instability–induced immune activation into suppression, promoting PARP inhibitor resistance. Cancer-associated fibroblasts (CAFs) mediate tumor progression in the tumor microenvironment (TME) and have been implicated in immunosuppression and therapy resistance across cancer types. Here, Liu et al. evaluated the role of CAFs in high-grade serous ovarian cancer resistance to PARP inhibitor treatment by integrating single-cell transcriptomics and epigenomics from patient samples. They identify a subtype of POSTN+ myofibroblast-like cancer-associated fibroblasts (myCAFs) that expand effector regulatory T cells and exhausted CD8+ T cells, suppressing immune activation and limiting PARP inhibitor efficacy. They show in mouse models that blocking these cells can overcome resistance, suggesting a promising treatment that warrants further study. —Dorothy Hallberg
Science Translational Medicine , résumé, 2026