ArticleProceedings of the National Academy of Sciences of the United States of America2020
Combining microenvironment normalization strategies to improve cancer immunotherapy.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 155 papers, 1 of them a synthesis 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
155 citing papers in PubMed, 1 synthesis or guideline pooled it, 268 citations in OpenAlex.
- The clinical trial landscape of bispecific antibodies in non-small cell lung cancer: mechanistic trends and developmental strategies.Frontiers in pharmacology · 2026Pooled it
- Anlotinib combined with chemoradiotherapy for postoperative isolated lymph node recurrence of ESCC: a phase II study.Frontiers in immunology · 2026Trial
- Sintilimab and anlotinib with gemcitabine plus cisplatin in advanced biliary tract cancer: SAGC a randomized phase 2 trial.Nature communications · 2025Trial
- Effect of Bevacizumab in Combination With Standard Oxaliplatin-Based Regimens in Patients With Metastatic Colorectal Cancer: A Randomized Clinical Trial.JAMA network open · 2021Trial
- Review
- A mechanical reprogramming: synergistic tumor microenvironment normalization improves nano-immunotherapy delivery in prostate cancer via multiphysics modeling.Drug delivery and translational research · 2026Article
- Computational Pathology Reveals Extracellular-Matrix Imaging Biomarkers of Therapy Response in Preclinical Breast Cancer.Cancers · 2026Article
- Targeting the αvβ5 Integrin Modifies the TGFβ-Rich Tumor Microenvironment of Pancreatic Cancer.Cancer research · 2026Article
- Mechanobiology-Driven Metabolic Reprogramming: Integrative Roles of YAP/TAZ Signaling and Extracellular Matrix Dynamics.Cell biology international · 2026Review
- A multiphysics computational model of focused ultrasound-enhanced drug delivery using temperature-sensitive liposomes.Biomechanics and modeling in mechanobiology · 2026Article
- Methodological innovations in perfusable vascular networks: Advancing high-density tissue models.Regenerative therapy · 2026Article
- Limited Immune-Mediated Efficacy of Anti-PD-L1/VEGF in EGFR-TKI-NaïveCurrent oncology (Toronto, Ont.) · 2026Article
- In vivo CAR-cell therapy: current challenges and emerging therapeutic advances.Molecular biomedicine · 2026Review
- Multiscale modeling reveals synergy between CCL19 and PD-1 blockade in reshaping the TNBC microenvironment.NPJ systems biology and applications · 2026Article
- Integrative QSP Modeling of Cancer Stem Cells in Triple-Negative Breast Cancer: Impacts on Tumor Immunity and Response to Immune Checkpoint Inhibitors.CPT: pharmacometrics & systems pharmacology · 2026Article
- Mechanisms of Resistance and Synergy: The Role of Tumor Microenvironment in HER2-Low Breast Cancer Therapy.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Antiemesis Corticosteroids Potentiate Checkpoint Blockade Efficacy by Normalizing the Immune Microenvironment in Metastatic Murine Breast Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Modulating tumor mechanics and vascular barriers to enhance chemotherapy efficacy in pancreatic tumors and melanoma.Journal of controlled release : official journal of the Controlled Release Society · 2026Article
- CXC Chemokine-Driven Vascular Reprogramming: Modulating Tumor Vasculature to Boost Therapeutic Response.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Vaccination-enabled immune readiness for checkpoint blockade.Frontiers in immunology · 2026Review
95 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
Advances in immunotherapy have revolutionized the treatment of multiple cancers. Unfortunately, tumors usually have impaired blood perfusion, which limits the delivery of therapeutics and cytotoxic immune cells to tumors and also results in hypoxia-a hallmark of the abnormal tumor microenvironment (TME)-that causes immunosuppression. We proposed that normalization of TME using antiangiogenic drugs and/or mechanotherapeutics can overcome these challenges. Recently, immunotherapy with checkpoint blockers was shown to effectively induce vascular normalization in some types of cancer. Although these therapeutic approaches have been used in combination in preclinical and clinical studies, their combined effects on TME are not fully understood. To identify strategies for improved immunotherapy, we have developed a mathematical framework that incorporates complex interactions among various types of cancer cells, immune cells, stroma, angiogenic molecules, and the vasculature. Model predictions were compared with the data from five previously reported experimental studies. We found that low doses of antiangiogenic treatment improve immunotherapy when the two treatments are administered sequentially, but that high doses are less efficacious because of excessive vessel pruning and hypoxia. Stroma normalization can further increase the efficacy of immunotherapy, and the benefit is additive when combined with vascular normalization. We conclude that vessel functionality dictates the efficacy of immunotherapy, and thus increased tumor perfusion should be investigated as a predictive biomarker of response to immunotherapy.
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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.