ArticleThe Journal of clinical investigation2025
Endothelial OX40 activation facilitates tumor cell escape from T cell surveillance through S1P/YAP-mediated angiogenesis.
Article in The Journal of clinical investigation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- A cell-free lipid sterosomal therapeutic enables bone regeneration via USP18-mediated noncanonical S1P signaling.Bioactive materials · 2026Article
- OX40 (TNFRSF4) Tracks Immune Infiltration in Small Cell Lung Cancer and Shows a Cohort-Specific, Non-Replicated Association with the POU2F3/SCLC-P Subtype: A Multi-Source In Silico Analysis.International journal of molecular sciences · 2026Article
- Lactate metabolism and lactylation in cancer: from pathogenesis to therapeutic advances.Signal transduction and targeted therapy · 2026Review
- Endothelial cell-derived IGFBP7 suppresses angiogenesis and tumor progression in colorectal cancer via the VAPA-TGF-β1 pathway.Journal of experimental & clinical cancer research : CR · 2026Article
- VIRMA/IGF2BP3-mediated ANLN upregulation promotes intrahepatic cholangiocarcinoma growth by forming a positive feedback loop with RhoA/YAP1/TEAD1 signaling pathway.Cell death & disease · 2026Article
- Unlocking the therapeutic potential of sphingolipids in wound healing: from molecular mechanisms to clinical applications.International journal of surgery (London, England) · 2026Review
- In vitro models to mimic tumor endothelial cell-mediated immune cell reprogramming in lung adenocarcinoma.Journal of experimental & clinical cancer research : CR · 2025Article
- DAPK1-positve macrophages facilitate immunosuppressive microenvironment and determine immunotherapy efficacy in colorectal cancer.Journal of translational medicine · 2025Article
- Sphingolipid Metabolism in the Pathogenesis of Hashimoto's Thyroiditis.International journal of molecular sciences · 2025Review
- OX40-OX40L Axis in Cutaneous T-Cell Lymphomas: Pathogenic, Prognostic, and Potential Therapeutic Perspectives.Biomolecules · 2025Review
- TNF superfamily molecules in atherosclerosis: mechanistic insights and therapeutic translation.Frontiers in immunology · 2025Review
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Authors and funding
21 authors.
Funding
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Abstract
Understanding the complexity of the tumor microenvironment is vital for improving immunotherapy outcomes. Here, we report that the T cell costimulatory molecule OX40 was highly expressed in tumor endothelial cells (ECs) and was negatively associated with the prognosis of patients, which is irrelevant to T cell activation. Analysis of conditional OX40 loss- and gain-of-function transgenic mice showed that OX40 signal in ECs counteracted the antitumor effects produced in T cells by promoting angiogenesis. Mechanistically, leucine-rich repeat-containing GPCR5 (Lgr5+ ) cancer stem cells induced OX40 expression in tumor ECs via EGF/STAT3 signaling. Activated OX40 interacted with Spns lysolipid transporter 2 (Spns2), obstructing the export of sphingosine 1-phosphate (S1P) and resulting in S1P intracellular accumulation. Increased S1P directly bound to Yes 1-associated protein (YAP), disrupting its interaction with large tumor suppressor kinase 1 (LATS1) and promoting YAP nuclear translocation. Finally, the YAP inhibitor verteporfin enhanced the antitumor effects of the OX40 agonist. Together, these findings reveal an unexpected protumor role of OX40 in ECs, highlighting the effect of nonimmune cell compartments on immunotherapy.
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