Tumor cell-derived IFN spatially reprograms osteopontin-enriched macrophage niches to promote PARP inhibitor resistance

J Clin Invest. 2026 Mar 6;136(8):e199035. doi: 10.1172/JCI199035. eCollection 2026 Apr 15.

Abstract

Poly (ADP-ribose) polymerase inhibitors (PARPis) benefit homologous recombination-deficient (HRD) malignancies, yet resistance remains a major challenge. Leveraging specimens from a prospective neoadjuvant niraparib monotherapy trial in treatment-naive, high-grade serous ovarian cancer, we integrated PhenoCycler-Fusion spatial profiling, scRNA-Seq, and multiplex immunohistochemistry to identify 2 therapeutic-modulated cellular neighborhoods: an IFN+ tumor cell-enriched niche that expands in resistant lesions and a niche enriched in tumor-associated macrophage (TAM) that persists but acquires enhanced immunosuppressive features. Mechanistically, sustained tumor cell-derived IFN induced osteopontin (SPP1) expression in TAMs via STAT signaling, creating immunosuppressive niches enriched in Tregs and myofibroblastic cancer-associated fibroblasts with intensified cell-cell interactions. SPP1 directly suppressed T cell signaling and effector function. High baseline SPP1+ cells predicted lower response rate (30.0% vs. 76.2%; P = 0.021) and shorter progression-free survival (median 13.5 vs. 28.3 months; P = 0.0006). In HRD mouse models, SPP1 blockade restored PARPi sensitivity, reversed acquired resistance, and enhanced T cell cytotoxicity-effects abrogated in immunodeficient mice, confirming immune dependence. These data establish a spatial IFN-SPP1 axis whereby persistent tumor cell IFN reprograms TAMs to promote PARPi resistance, position SPP1 as a key therapeutic target and prognostic biomarker for this therapy, and underscore therapeutic potential of microenvironment-targeted strategies to overcome PARPi resistance.

Keywords: Biomarkers; Cancer; Immunology; Immunotherapy; Oncology.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm*
  • Female
  • Humans
  • Interferons* / immunology
  • Interferons* / metabolism
  • Macrophages* / immunology
  • Macrophages* / metabolism
  • Macrophages* / pathology
  • Mice
  • Neoplasm Proteins* / genetics
  • Neoplasm Proteins* / immunology
  • Neoplasm Proteins* / metabolism
  • Osteopontin* / genetics
  • Osteopontin* / immunology
  • Osteopontin* / metabolism
  • Ovarian Neoplasms* / drug therapy
  • Ovarian Neoplasms* / genetics
  • Ovarian Neoplasms* / immunology
  • Ovarian Neoplasms* / metabolism
  • Ovarian Neoplasms* / pathology
  • Poly(ADP-ribose) Polymerase Inhibitors* / pharmacology
  • Tumor Microenvironment* / drug effects
  • Tumor-Associated Macrophages* / immunology
  • Tumor-Associated Macrophages* / metabolism
  • Tumor-Associated Macrophages* / pathology

Substances

  • Osteopontin
  • Poly(ADP-ribose) Polymerase Inhibitors
  • SPP1 protein, human
  • Interferons
  • Neoplasm Proteins