ArticleCancer research2015
NOS Inhibition Modulates Immune Polarization and Improves Radiation-Induced Tumor Growth Delay.
Article in Cancer research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers, 2 of them syntheses that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
31 citing papers in PubMed, 2 syntheses or guidelines pooled it, 49 citations in OpenAlex.
- The microbiome-nitric oxide axis in cancer immunotherapy: a targeted qualitative systematic review of mechanistic and translational evidence.Frontiers in immunology · 2026Pooled it
- Modulation of tumor-associated macrophage activity with radiation therapy: a systematic review.Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al] · 2023Pooled it
- NOS2 and COX2 impact the spatial landscape of CD8Redox biology · 2026Review
- Loss of inducible nitric oxide synthase promotes Kras/Pten-driven lung tumorigenesis.Frontiers in cell and developmental biology · 2026Article
- Elevated tumor NOS2/COX2 promotes immunosuppressive phenotypes associated with poor survival in ER- breast cancer.JCI insight · 2025Article
- Targeting Neuronal Nitric Oxide Synthase (nNOS) as a Novel Approach to Enhancing the Anti-Melanoma Activity of Immune Checkpoint Inhibitors.Pharmaceutics · 2025Article
- Tumor NOS2 and COX2 Spatial Juxtaposition with CD8+ T Cells Promote Metastatic and Cancer Stem Cell Niches that Lead to Poor Outcome in ER- Breast Cancer.Cancer research communications · 2024Article
- Adjuvant COX inhibition augments STING signaling and cytolytic T cell infiltration in irradiated 4T1 tumors.JCI insight · 2024Article
- NOS2 and COX2 Provide Key Spatial Targets that Determine Outcome in ER- Breast Cancer.bioRxiv : the preprint server for biology · 2023Article
- Nitric Oxide Modulates Metabolic Processes in the Tumor Immune Microenvironment.International journal of molecular sciences · 2021Review
- Myeloid cell-derived PROS1 inhibits tumor metastasis by regulating inflammatory and immune responses via IL-10.The Journal of clinical investigation · 2021Article
- Macrophages and Extracellular Matrix in Breast Cancer: Partners in Crime or Protective Allies?Frontiers in oncology · 2021Review
- The Critical Role of Tetrahydrobiopterin (BH4) Metabolism in Modulating Radiosensitivity: BH4/NOS Axis as an Angel or a Devil.Frontiers in oncology · 2021Review
- Depletion of microglia exacerbates injury and impairs function recovery after spinal cord injury in mice.Cell death & disease · 2020Article
- Inducible nitric oxide synthase-derived extracellular nitric oxide flux regulates proinflammatory responses at the single cell level.Redox biology · 2020Article
- Baicalin Inhibits Influenza A Virus InfectionFrontiers in pharmacology · 2020Article
- Role of nitric oxide in pancreatic cancer cells exhibiting the invasive phenotype.Redox biology · 2019Article
- Molecular Mechanisms of Nitric Oxide in Cancer Progression, Signal Transduction, and Metabolism.Antioxidants & redox signaling · 2019Review
- Endothelial nitric oxide synthase limits host immunity to control disseminated Candida albicans infections in mice.PloS one · 2019Article
- Understanding the tumour micro-environment communication network from an NOS2/COX2 perspective.British journal of pharmacology · 2019Review
Corrections and comments
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Authors and funding
18 authors at 3 institutions in 2 countries.
Funding
Abstract
Nitric oxide synthases (NOS) are important mediators of progrowth signaling in tumor cells, as they regulate angiogenesis, immune response, and immune-mediated wound healing. Ionizing radiation (IR) is also an immune modulator and inducer of wound response. We hypothesized that radiation therapeutic efficacy could be improved by targeting NOS following tumor irradiation. Herein, we show enhanced radiation-induced (10 Gy) tumor growth delay in a syngeneic model (C3H) but not immunosuppressed (Nu/Nu) squamous cell carcinoma tumor-bearing mice treated post-IR with the constitutive NOS inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME). These results suggest a requirement of T cells for improved radiation tumor response. In support of this observation, tumor irradiation induced a rapid increase in the immunosuppressive Th2 cytokine IL10, which was abated by post-IR administration of L-NAME. In vivo suppression of IL10 using an antisense IL10 morpholino also extended the tumor growth delay induced by radiation in a manner similar to L-NAME. Further examination of this mechanism in cultured Jurkat T cells revealed L-NAME suppression of IR-induced IL10 expression, which reaccumulated in the presence of exogenous NO donor. In addition to L-NAME, the guanylyl cyclase inhibitors ODQ and thrombospondin-1 also abated IR-induced IL10 expression in Jurkat T cells and ANA-1 macrophages, which further suggests that the immunosuppressive effects involve eNOS. Moreover, cytotoxic Th1 cytokines, including IL2, IL12p40, and IFNγ, as well as activated CD8(+) T cells were elevated in tumors receiving post-IR L-NAME. Together, these results suggest that post-IR NOS inhibition improves radiation tumor response via Th1 immune polarization within the tumor microenvironment.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.