The vascular–immune interface in breast cancer: normalization strategies, combination therapy, and biomarkers
- 1Thyroid and Breast Surgery, The Second Affiliated Hospital of Zunyi Medical University
- 2Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Zunyi Medical University
Abstract
Immune checkpoint inhibitors have improved outcomes in selected patients with breast cancer, particularly those with triple-negative disease, but most tumors remain refractory. Abnormal tumor vasculature is one contributor to this resistance. Disorganized, hyperpermeable vessels produce heterogeneous perfusion, hypoxia, acidosis, and elevated interstitial pressure; these changes impede drug delivery and lymphocyte trafficking while favoring regulatory T cells, myeloid-derived suppressor cells, and dysfunctional antigen presentation. Anti-angiogenic therapy can transiently reverse part of this phenotype. When dose and timing are appropriate, a vascular-normalization window improves perfusion and oxygenation, restores endothelial adhesiveness, and creates conditions in which chemotherapy and immune checkpoint blockade may work more effectively. This framework is biologically compelling, but clinical evidence in breast cancer remains uneven: activity has been reported in several early-phase combination studies, whereas large trials of bevacizumab-containing regimens have not consistently improved overall survival. Candidate biomarkers—including VEGF/VEGFR signaling, angiopoietin–Tie2 activity, PD-L1, high endothelial venules, tertiary lymphoid structures, circulating cytokines, and spatial patterns of immune exclusion—remain exploratory and are limited by assay variability and temporal heterogeneity. This narrative review examines the vascular – immune interface across breast cancer subtypes, distinguishes mechanistic rationale from clinical proof, and identifies priorities for biomarker-guided trials designed to define dose, sequence, and the normalization window.
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BibTeX
@article{zhang2026vascularimmune,
title = {{The vascular–immune interface in breast cancer: normalization strategies, combination therapy, and biomarkers}},
author = {Yujing Zhang and Cai Yulan and Kaiguo Long and Qi Wang and Chuyu Liu and Feng Zeng},
journal = {Frontiers in Oncology},
year = {2026},
month = oct,
doi = {10.3389/fonc.2026.1962446},
url = {https://www.frontiersin.org/articles/10.3389/fonc.2026.1962446/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The vascular–immune interface in breast cancer: normalization strategies, combination therapy, and biomarkers
AU - Yujing Zhang
AU - Cai Yulan
AU - Kaiguo Long
AU - Qi Wang
AU - Chuyu Liu
AU - Feng Zeng
PY - 2026
DA - 2026/10/22
JO - Frontiers in Oncology
DO - 10.3389/fonc.2026.1962446
UR - https://www.frontiersin.org/articles/10.3389/fonc.2026.1962446/full
AB - Immune checkpoint inhibitors have improved outcomes in selected patients with breast cancer, particularly those with triple-negative disease, but most tumors remain refractory. Abnormal tumor vasculature is one contributor to this resistance. Disorganized, hyperpermeable vessels produce heterogeneous perfusion, hypoxia, acidosis, and elevated interstitial pressure; these changes impede drug delivery and lymphocyte trafficking while favoring regulatory T cells, myeloid-derived suppressor cells, and dysfunctional antigen presentation. Anti-angiogenic therapy can transiently reverse part of this phenotype. When dose and timing are appropriate, a vascular-normalization window improves perfusion and oxygenation, restores endothelial adhesiveness, and creates conditions in which chemotherapy and immune checkpoint blockade may work more effectively. This framework is biologically compelling, but clinical evidence in breast cancer remains uneven: activity has been reported in several early-phase combination studies, whereas large trials of bevacizumab-containing regimens have not consistently improved overall survival. Candidate biomarkers—including VEGF/VEGFR signaling, angiopoietin–Tie2 activity, PD-L1, high endothelial venules, tertiary lymphoid structures, circulating cytokines, and spatial patterns of immune exclusion—remain exploratory and are limited by assay variability and temporal heterogeneity. This narrative review examines the vascular – immune interface across breast cancer subtypes, distinguishes mechanistic rationale from clinical proof, and identifies priorities for biomarker-guided trials designed to define dose, sequence, and the normalization window.
SN - 2234-943X
ER -