ArticleProceedings of the National Academy of Sciences of the United States of America2012
Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 678 papers, 5 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
678 citing papers in PubMed, 5 syntheses or guidelines pooled it, 1,064 citations in OpenAlex.
- Pooled it
- Treatment-Related and Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitor-Based Combination Therapies for Breast Cancer: A Systematic Review and Meta-Analysis.Thoracic cancer · 2026Pooled it
- Mapping research trends in macrophage polarization and immunotherapeutic potential in prostate cancer: a bibliometric and visual analysis.Frontiers in oncology · 2026Pooled it
- Immune checkpoint inhibitor integration in locoregionally advanced nasopharyngeal carcinoma: a prospective evidence synthesis on efficacy, safety, and therapeutic optimization.Frontiers in immunology · 2026Pooled it
- Antiangiogenic therapy exerts antitumor effects by altering the tumor microenvironment: bibliometric analysis.Frontiers in immunology · 2024Pooled it
- Neoadjuvant camrelizumab plus chemotherapy or apatinib for resectable stage IIA-IIIA NSCLC: a multicenter, two-arm, phase II exploratory trial.BMC medicine · 2025Trial
- Sintilimab and anlotinib with gemcitabine plus cisplatin in advanced biliary tract cancer: SAGC a randomized phase 2 trial.Nature communications · 2025Trial
- Reshaping the tumor microenvironment of cold soft-tissue sarcomas with anti-angiogenics: a phase 2 trial of regorafenib combined with avelumab.Signal transduction and targeted therapy · 2025Trial
- Regorafenib plus avelumab in advanced gastroenteropancreatic neuroendocrine neoplasms: a phase 2 trial and correlative analysis.Nature cancer · 2025Trial
- Toripalimab plus anlotinib in patients with recurrent or metastatic nasopharyngeal carcinoma: A multicenter, single-arm phase 2 trial (TORAL).Cell reports. Medicine · 2024Trial
- Metronomic chemotherapy plus anti-PD-1 in metastatic breast cancer: a Bayesian adaptive randomized phase 2 trial.Nature medicine · 2024Trial
- A gut microbiota rheostat forecasts responsiveness to PD-L1 and VEGF blockade in mesothelioma.Nature communications · 2024Trial
- Immunomic longitudinal profiling of the NeoPembrOv trial identifies drivers of immunoresistance in high-grade ovarian carcinoma.Nature communications · 2024Trial
- Neoadjuvant camrelizumab (an anti-PD-1 antibody) plus chemotherapy or apatinib (a VEGFR-2 inhibitor) for initially unresectable stage II-III non-small-cell lung cancer: a multicentre, two-arm, phase 2 exploratory study.Signal transduction and targeted therapy · 2024Trial
- Trial
- Camrelizumab and apatinib plus induction chemotherapy and concurrent chemoradiotherapy in stage N3 nasopharyngeal carcinoma: a phase 2 clinical trial.Nature communications · 2024Trial
- NCI10066: a Phase 1/2 study of olaparib in combination with ramucirumab in previously treated metastatic gastric and gastroesophageal junction adenocarcinoma.British journal of cancer · 2024Trial
- Linking preclinical models with functional imaging and artificial intelligence to decode tumor angiogenesis.Pharmacological reports : PR · 2026Review
- CD8⁺ T Cell infiltration and spatial organization in cancer: mechanisms, barriers, and therapeutic strategies.Molecular biomedicine · 2026Review
- Tumor microenvironment-rearranging Nanoassemblies overcome angiogenesis-immunotherapy resistance to potentiate osteosarcoma treatment.Materials today. Bio · 2026Article
618 more citing papers are in PubMed but not listed here.
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Authors and funding
17 authors at 2 institutions in 1 country.
Funding
Abstract
The recent approval of a prostate cancer vaccine has renewed hope for anticancer immunotherapies. However, the immunosuppressive tumor microenvironment may limit the effectiveness of current immunotherapies. Antiangiogenic agents have the potential to modulate the tumor microenvironment and improve immunotherapy, but they often are used at high doses in the clinic to prune tumor vessels and paradoxically may compromise various therapies. Here, we demonstrate that targeting tumor vasculature with lower vascular-normalizing doses, but not high antivascular/antiangiogenic doses, of an anti-VEGF receptor 2 (VEGFR2) antibody results in a more homogeneous distribution of functional tumor vessels. Furthermore, lower doses are superior to the high doses in polarizing tumor-associated macrophages from an immune inhibitory M2-like phenotype toward an immune stimulatory M1-like phenotype and in facilitating CD4(+) and CD8(+) T-cell tumor infiltration. Based on this mechanism, scheduling lower-dose anti-VEGFR2 therapy with T-cell activation induced by a whole cancer cell vaccine therapy enhanced anticancer efficacy in a CD8(+) T-cell-dependent manner in both immune-tolerant and immunogenic murine breast cancer models. These findings indicate that vascular-normalizing lower doses of anti-VEGFR2 antibody can reprogram the tumor microenvironment away from immunosuppression toward potentiation of cancer vaccine therapies. Given that the combinations of high doses of bevacizumab with chemotherapy have not improved overall survival of breast cancer patients, our study suggests a strategy to use antiangiogenic agents in breast cancer more effectively with active immunotherapy and potentially other anticancer therapies.
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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.