ArticleJournal for immunotherapy of cancer2023
STING agonism overcomes STAT3-mediated immunosuppression and adaptive resistance to PARP inhibition in ovarian cancer.
Article in Journal for immunotherapy of cancer, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 87 citations in OpenAlex.
- Subtype-specific mechanisms of lipid metabolism in gynecological malignancies and novel targeted intervention strategies (Review).Oncology letters · 2026Review
- Review
- PARP inhibitor YCH1899 activates type I interferon signaling and synergizes with STING agonists in BRCA-proficient tumors.Molecular biomedicine · 2026Article
- STAT1 and STAT3 signaling in ovarian cancer: prognostic biomarkers and therapeutic targets.BMC cancer · 2026Article
- Detection of nuclear STING in cultured human cells and in the normal and cancer tissues.iScience · 2026Article
- NEK1 Promotes Ovarian Cancer Progression via p53 Suppression While Enhancing Sensitivity to Genotoxic Therapy.Current issues in molecular biology · 2026Article
- High expression of STAT3 and PD-L1 predicts poor prognosis for laryngeal squamous cell carcinoma.Scientific reports · 2026Article
- Deltex E3 ubiquitin ligase 2 potentiates STING-mediated type I interferon response by K63-linked ubiquitination.Cell death & disease · 2026Article
- Interplay Between Poly(ADP-ribosyl)ation and Specific Inner Cellular Events That Suggest Combination Strategies for Overcoming PARP Inhibitor Resistance.Pharmaceutics · 2026Review
- Dual FAK and EPHA2 targeting by brigatinib tackles PARP inhibitor adaptive survival response in high-grade serous ovarian cancer.Science translational medicine · 2026Article
- Hypoxia-driven remodeling of SELENOPNature communications · 2026Article
- Mechanisms of resistance to PARP inhibitors in advanced epithelial ovarian cancer: biological determinants and therapeutic implications.Frontiers in oncology · 2026Review
- Integrative Analysis Reveals Genes Causal Relation with Ovarian Cancer and aging.Current topics in medicinal chemistry · 2026Article
- STING signaling pathway: An oasis in the glioblastoma immune desert.Theranostics · 2026Review
- Shaping the future one slice at a time: How 3D organotypic tumour slice models are driving drug discovery in ovarian cancer.Translational oncology · 2026Review
- CD44v5 enhances the IL-4/IL-4Rα/STAT6/SAM68 aix inducing M2 polarization and promoting triple-negative breast cancer progression.Cancer biology & therapy · 2025Article
- cGAS-STING signaling pathway as a therapeutic target in human diseases.Chinese medical journal · 2025Review
- Tumor-associated macrophages in cancer: from mechanisms to application.Molecular biomedicine · 2025Review
- DNA damaging agents boost the transcription of endothelin A receptor in high-grade serous ovarian cancer.Journal of experimental & clinical cancer research : CR · 2025Article
- Post-translational modifications in ovarian cancer: implications for immunotherapy: a mini-review.Journal of ovarian research · 2025Review
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Authors and funding
19 authors at 6 institutions in 3 countries.
Funding
Abstract
backgroundPoly (ADP-ribose) polymerase (PARP) inhibition (PARPi) has demonstrated potent therapeutic efficacy in patients with BRCA-mutant ovarian cancer. However, acquired resistance to PARPi remains a major challenge in the clinic.
methodsPARPi-resistant ovarian cancer mouse models were generated by long-term treatment of olaparib in syngeneic Brca1-deficient ovarian tumors. Signal transducer and activator of transcription 3 (STAT3)-mediated immunosuppression was investigated
resultsIn this study, we uncover an adaptive resistance mechanism to PARP inhibition mediated by tumor-associated macrophages (TAMs) in the TME. Markedly increased populations of protumor macrophages are found in BRCA-deficient ovarian tumors that rendered resistance to PARPi in both murine models and patients. Mechanistically, PARP inhibition elevates the STAT3 signaling pathway in tumor cells, which in turn promotes protumor polarization of TAMs. STAT3 ablation in tumor cells mitigates polarization of protumor macrophages and increases tumor-infiltrating T cells on PARP inhibition. These findings are corroborated in patient-derived, PARPi-resistant BRCA1-mutant ovarian tumors. Importantly, STING agonists reshape the immunosuppressive TME by reprogramming myeloid cells and overcome the TME-dependent adaptive resistance to PARPi in ovarian cancer. This effect is further enhanced by addition of the programmed cell death protein-1 blockade.
conclusionsWe elucidate an adaptive immunosuppression mechanism rendering resistance to PARPi in BRCA1-mutant ovarian tumors. This is mediated by enrichment of protumor TAMs propelled by PARPi-induced STAT3 activation in tumor cells. We also provide a new strategy to reshape the immunosuppressive TME with STING agonists and overcome PARPi resistance in ovarian cancer.
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