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Cited by 190Angiogenesis and VEGF in CancerCancer Immunotherapy and BiomarkersCancer Cells and Metastasis

The DOI matches its Crossref record; 171 of the 172 references it cites were found in a registry or an index.

Normalization of the tumor microenvironment by harnessing vascular and immune modulation to achieve enhanced cancer therapy

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Choi, Yechan, Jung, Keehoon·2023·Experimental & Molecular Medicine
DOI 10.1038/s12276-023-01114-wPMC PMC10689787
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Abstract

Solid tumors are complex entities that actively shape their microenvironment to create a supportive environment for their own growth. Angiogenesis and immune suppression are two key characteristics of this tumor microenvironment. Despite attempts to deplete tumor blood vessels using antiangiogenic drugs, extensive vessel pruning has shown limited efficacy. Instead, a targeted approach involving the judicious use of drugs at specific time points can normalize the function and structure of tumor vessels, leading to improved outcomes when combined with other anticancer therapies. Additionally, normalizing the immune microenvironment by suppressing immunosuppressive cells and activating immunostimulatory cells has shown promise in suppressing tumor growth and improving overall survival. Based on these findings, many studies have been conducted to normalize each component of the tumor microenvironment, leading to the development of a variety of strategies. In this review, we provide an overview of the concepts of vascular and immune normalization and discuss some of the strategies employed to achieve these goals.

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Fig. 1 Vascular normalization: Restoring vascular integrity to enhance oxygenation and therapeutic drug delivery in tumor vasculature. a Comparison of vascular normalization with current therapies using AATs. Tumors exhibit abnormal vasculature, characterized by irregularly shaped endothelial cells, sparse pericyte coverage, and compression by tumor cells and their extracellular matrices, resulting in poorly perfused vessels (middle panel). Current antiangiogenic therapies, mainly aimed at depleting the tumor vasculature, often lead to excessive vessel pruning, causing hypoxia and limited drug delivery (left panel). Vascular normalization strategies aim to restore vascular integrity, improving oxygenation and enhancing the delivery of therapeutic drugs (right panel). b Various vascular normalization methods. Vascular normalization can be induced by targeting VEGF signaling or Ang–Tie signaling in endothelial cells or oncogenic signaling in cancer cells. Immune checkpoint blockade can induce vascular normalization through the function of CD8+ or CD4 + T cells and the accumulation of eosinophils. AAT, antiangiogenic therapy; IFP, interstitial fluid pressure; CAF, cancer-associated fibroblast; ECM, extracellular matrix; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; PLCγ, phospholipase γ; PI3K, phosphoinositide 3-kinase; Ang2, angiopoietin 2; EGFR, epidermal growth factor receptor.
Fig. 1 Vascular normalization: Restoring vascular integrity to enhance oxygenation and therapeutic drug delivery in tumor vasculature. a Comparison of vascular normalization with current therapies using AATs. Tumors exhibit abnormal vasculature, characterized by irregularly shaped endothelial cells, sparse pericyte coverage, and compression by tumor cells and their extracellular matrices, resulting in poorly perfused vessels (middle panel). Current antiangiogenic therapies, mainly aimed at depleting the tumor vasculature, often lead to excessive vessel pruning, causing hypoxia and limited drug delivery (left panel). Vascular normalization strategies aim to restore vascular integrity, improving oxygenation and enhancing the delivery of therapeutic drugs (right panel). b Various vascular normalization methods. Vascular normalization can be induced by targeting VEGF signaling or Ang–Tie signaling in endothelial cells or oncogenic signaling in cancer cells. Immune checkpoint blockade can induce vascular normalization through the function of CD8+ or CD4 + T cells and the accumulation of eosinophils. AAT, antiangiogenic therapy; IFP, interstitial fluid pressure; CAF, cancer-associated fibroblast; ECM, extracellular matrix; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; PLCγ, phospholipase γ; PI3K, phosphoinositide 3-kinase; Ang2, angiopoietin 2; EGFR, epidermal growth factor receptor.CC BY · PubMed Central
Fig. 2 Immune normalization: Modulating the tumor immune microenvironment to suppress immunosuppression and recruit antitumoral immune cells. Tumors employ mechanisms to enhance immunosuppression, including recruiting immunosuppressive leukocytes and suppressing the function of antitumoral immune cells. Chemotaxis of classical monocytes (CMs) is facilitated by the CCL2–CCR2 axis, and these CMs secrete cytokines such as IL-6, that promote tumor metastasis and therapy resistance. Tumors secrete CX3CL1, recruiting nonclassical monocytes (NCMs) that, in turn, can recruit neutrophils via the CXCL5–CXCR2 axis. Both CMs and NCMs secrete immunosuppressive cytokines, including IL-10. M2-like TAMs further suppress the antitumoral immune response by secreting cytokines such as IL-4. Immune checkpoints employed by tumors dampen the function of effector T cells. Strategies for immune normalization include inhibiting monocyte recruitment using anti-CCL2 antibodies/siRNAs, CXCR4 blockers, or CCR2 inhibition. Enhancing effector T-cell function can be achieved through cancer vaccines or immune checkpoint blockade (ICB). Additionally, oncolytic viruses can target tumor cells, inducing their lysis and recruiting antitumoral immune cells. NK, natural killer; CM, classical monocyte; NCM, nonclassical monocyte; TAM, tumor-associated macrophage; ROS, reactive oxygen species; ICB, immune checkpoint blockade; GM-CSF, granulocyte-macrophage colony-stimulating factor.
Fig. 2 Immune normalization: Modulating the tumor immune microenvironment to suppress immunosuppression and recruit antitumoral immune cells. Tumors employ mechanisms to enhance immunosuppression, including recruiting immunosuppressive leukocytes and suppressing the function of antitumoral immune cells. Chemotaxis of classical monocytes (CMs) is facilitated by the CCL2–CCR2 axis, and these CMs secrete cytokines such as IL-6, that promote tumor metastasis and therapy resistance. Tumors secrete CX3CL1, recruiting nonclassical monocytes (NCMs) that, in turn, can recruit neutrophils via the CXCL5–CXCR2 axis. Both CMs and NCMs secrete immunosuppressive cytokines, including IL-10. M2-like TAMs further suppress the antitumoral immune response by secreting cytokines such as IL-4. Immune checkpoints employed by tumors dampen the function of effector T cells. Strategies for immune normalization include inhibiting monocyte recruitment using anti-CCL2 antibodies/siRNAs, CXCR4 blockers, or CCR2 inhibition. Enhancing effector T-cell function can be achieved through cancer vaccines or immune checkpoint blockade (ICB). Additionally, oncolytic viruses can target tumor cells, inducing their lysis and recruiting antitumoral immune cells. NK, natural killer; CM, classical monocyte; NCM, nonclassical monocyte; TAM, tumor-associated macrophage; ROS, reactive oxygen species; ICB, immune checkpoint blockade; GM-CSF, granulocyte-macrophage colony-stimulating factor.CC BY · PubMed Central

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Metadata

Authors
Choi, Y., & Jung, K.
Affiliations
Seoul National University (KR)
Corresponding author
Jung, Keehoon
ORCID
Jung, Keehoon
Venue
Experimental & Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2023-11-01
Volume
55
Issue
11
Pages
2308-2319
ISSN
  • 1226-3613 (ISSN-L)
  • 2092-6413
DOI
10.1038/s12276-023-01114-w
PMC
PMC10689787
OpenAlex
W4388081006
Cited by
188
References
172
Citations by year
2026: 109 · 2025: 47 · 2024: 32
FWCI
4.97
Type
journal article
Language
en
Open access
Licence
Locations
  • Experimental & Molecular Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Research Foundation
  • Seoul National University
  • National Research Foundation of Korea (2021M3A9I4026318, NRF-2021M3A9I4026318)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
tumor microenvironment, tumor vasculature normalization, angiogenesis, anti-angiogenic therapy, immunosuppression, combination cancer therapy
MeSH terms
Humans, Immunotherapy, Neoplasms, Neovascularization, Pathologic, Angiogenesis Inhibitors, Tumor Microenvironment

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