ArticleJournal for immunotherapy of cancer2023
Synergistic therapeutic combination with a CAF inhibitor enhances CAR-NK-mediated cytotoxicity via reduction of CAF-released IL-6.
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 44 papers.
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Who cites it
44 citing papers in PubMed, 57 citations in OpenAlex.
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- Engineering strategies to address immune and delivery barriers in pancreatic ductal adenocarcinoma: a barrier-matched translational framework.Frontiers in immunology · 2026Review
- CAR-NK Engineering to Overcome TME Barriers.Cells · 2025Review
- Cancer-associated fibroblasts in the tumor microenvironment: heterogeneity, crosstalk mechanisms, and therapeutic implications.Molecular cancer · 2025Review
- Harnessing the power of cancer-associated fibroblasts to revolutionize pancreatic cancer treatment.Cancer biology & medicine · 2025Review
- Emerging role of cancer-associated fibroblasts in the premetastatic niche.Molecular cancer · 2025Review
- CAR NK cell therapy for solid tumors: potential and challenges.Antibody therapeutics · 2025Review
- Plasticity and Functional Heterogeneity of Cancer-Associated Fibroblasts.Cancer research · 2025Review
- Intraperitoneal infusion of NKG2D CAR-NK cells induces endogenous CD8Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Cancer-Associated Fibroblasts: Heterogeneity, Cancer Pathogenesis, and Therapeutic Targets.MedComm · 2025Review
- Dual-Faced Role of GDF6 in Cancer: Mechanistic Insights into Its Context-Dependent Regulation of Metastasis and Immune Evasion Across Human Malignancies.Current issues in molecular biology · 2025Article
Corrections and comments
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Authors and funding
13 authors at 5 institutions in 1 country.
Funding
Abstract
backgroundCancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) contribute to an impaired functionality of natural killer (NK) cells that have emerged as a promising therapeutic modality. The interaction between CAFs and NK cells within the TME exerts major inhibitory effects on immune responses, indicating CAF-targeted therapies as potential targets for effective NK-mediated cancer killing.
methodsTo overcome CAF-induced NK dysfunction, we selected an antifibrotic drug, nintedanib, for synergistic therapeutic combination. To evaluate synergistic therapeutic efficacy, we established an in vitro 3D Capan2/patient-derived CAF spheroid model or in vivo mixed Capan2/CAF tumor xenograft model. The molecular mechanism of NK-mediated synergistic therapeutic combination with nintedanib was revealed through in vitro experiments. In vivo therapeutic combination efficacy was subsequently evaluated. Additionally, the expression score of target proteins was measured in patient-derived tumor sections by the immunohistochemical method.
resultsNintedanib blocked the platelet-derived growth factor receptor β (PDGFRβ) signaling pathway and diminished the activation and growth of CAFs, markedly reducing CAF-secreted IL-6. Moreover, coadministration of nintedanib improved the mesothelin (MSLN) targeting chimeric antigen receptor-NK-mediated tumor killing abilities in CAF/tumor spheroids or a xenograft model. The synergistic combination resulted in intense NK infiltration in vivo. Nintedanib alone exerted no effects, whereas blockade of IL-6 trans-signaling ameliorated the function of NK cells. The combination of the expression of MSLN and the PDGFRβ
conclusionOur strategy against PDGFRβ
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