Genomic instability drives POSTN + myofibroblasts via STING-WNT axis to promote immunosuppression and PARPi resistance in ovarian cancer

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 (eT reg 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 eT reg 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 eT reg 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.