From vascular normalization to VEGF-independent escape: multi-omics-defined angio-immune ecosystem states

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.