From vascular normalization to VEGF-independent escape: multi-omics-defined angio-immune ecosystem states
Baolai Li1, Haitao Song1, Yongmei Dai1
1Department of Obstetrics, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, Shandong, China.
Abstract:
Anti-angiogenic therapy and immune checkpoint blockade can synergize, yet benefits are frequently transient, implying that resistance reflects ecosystem-level reprogramming rather than failure of a single pathway. Here we define angio-immune ecosystem states as reproducible tumor microenvironment configurations that couple vascular function, immune composition, and spatial architecture. We summarize four resistance-associated states: endothelial-stromal gatekeeping with immune exclusion, a time-limited normalization window, hypoxia/myeloid-driven rebound immunosuppression, and VEGF-independent perfusion escape via vessel co-option, vasculogenic mimicry, or intussusceptive remodeling. Finally, we propose an interpretable measurement stack, integrating bulk transcriptional modules, single-cell-anchored cell-state programs, and spatial neighborhood features, to enable cross-cohort stratification and longitudinal tracking. This framework supports state-matched combinations by linking therapeutic resistance to distinct spatial configurations of the intravascular lumen, endothelial interface, perivascular niche, stromal-parenchymal boundary, and immune-cell trafficking axis.
Insights
Tumor resistance to anti-angiogenic therapy and immune checkpoint blockade involves complex angio-immune ecosystem states. Understanding these states is key to developing effective, long-term cancer treatments.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Anti-angiogenic therapy and immune checkpoint blockade are crucial cancer treatments.
- Therapeutic benefits are often transient, suggesting resistance mechanisms.
- Resistance may stem from ecosystem-level tumor microenvironment reprogramming.
Purpose of the Study:
- To define and characterize angio-immune ecosystem states associated with therapeutic resistance.
- To identify specific configurations of vascular, immune, and spatial factors.
- To develop a framework for stratifying patients and tracking resistance longitudinally.
Main Methods:
- Integration of bulk transcriptional modules.
- Application of single-cell-anchored cell-state programs.
- Analysis of spatial neighborhood features.
Main Results:
- Identified four resistance-associated angio-immune ecosystem states.
- These states involve endothelial-stromal gatekeeping, limited normalization windows, hypoxia/myeloid-driven immunosuppression, and VEGF-independent perfusion escape.
- Linked resistance to specific spatial configurations within the tumor microenvironment.
Conclusions:
- Angio-immune ecosystem states provide a framework for understanding transient therapeutic benefits.
- This framework enables state-matched combination therapies.
- Linking resistance to spatial configurations can guide treatment strategies.
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