Targeting the Myeloid–Angiogenic Axis in the Metastatic Tumor Microenvironment: Mechanisms, Model Systems, and Therapeutic Sensitization

Metastatic progression across solid and gastrointestinal malignancies is driven by a cooperative interplay between the immune and vascular compartments. Rather than acting independently, tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and pro-angiogenic endothelial cells establish reciprocal signaling circuits that govern vascular remodeling, heighten tissue hypoxia, and enforce physical and functional barriers against cytotoxic T-cell infiltration. This coordinated myeloid–angiogenic crosstalk serves as a principal engine of immune exclusion and primary resistance to immune checkpoint blockade.While syngeneic models, patient-derived xenografts (PDX), and advanced organoid systems have provided crucial windows into these dynamics, dissecting how phenotypic transitions within myeloid subpopulations shape the tumor vasculature remains an active frontier. Overcoming resistance in advanced and metastatic disease necessitates rational combination strategies capable of simultaneously normalizing aberrant tumor vessels, reprogramming immunosuppressive myeloid subsets, and re-engaging systemic antitumor immunity.This Research Topic focuses on deciphering the molecular and cellular mechanisms underpinning the myeloid–angiogenic axis across metastatic niches and solid tumors. We aim to highlight how multi-omic spatial mapping, rigorous preclinical cross-validation, and rational therapeutic combinations (e.g., dual anti-angiogenic/myeloid-targeting agents paired with checkpoint inhibitors) can overcome immune exclusion.We welcome Original Research, Reviews, Mini-Reviews, and Perspective articles covering, but not limited to, the following themes:• Mechanisms of Myeloid–Vascular Crosstalk: Molecular pathways through which TAMs, monocytes, and MDSCs regulate tumor angiogenesis, endothelial anergy, and vessel abnormalization.• Hypoxia, Extracellular Matrix, and Immune Exclusion: How myeloid-driven vascular dysfunction and matrix remodeling establish physical barriers to T-cell trafficking.• Myeloid Agonism and Microenvironment Reprogramming: Strategies employing CD40 agonists, CSF1R inhibitors, or metabolic modulators to shift myeloid cells from pro-angiogenic/suppressive to immunostimulatory phenotypes.• Model Systems and Translational Validation: Interrogating the myeloid–vascular niche across complementary platforms (syngeneic mouse models, PDX, vascularized organ-on-a-chip, and patient-derived organoids).• Spatial Multi-Omics and Vascular Profiling: Spatial transcriptomic, single-cell, and high-dimensional imaging approaches resolving spatial relationships between immune cells, pericytes, and endothelial subsets.• Dual-Targeting and Combination Therapies: Preclinical rationale and clinical evaluation of anti-angiogenic agents (e.g., VEGF/VEGFR, angiopoietin inhibitors) synergized with myeloid modulators and immune checkpoint inhibitors. Topic editors: Huan Ren, Manisha Singh Source: https://www.frontiersin.org/research-topics/86109/targeting-the-myeloid-angiogenic-axis-in-the-metastatic-tumor-microenvironment-mechanisms-model-systems-and-therapeutic-sensitization