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

Abstract

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.