Immune-excluded and immune-suppressive tumor microenvironments: mechanisms, spatial biomarkers, and therapeutic rewiring

<h4>Background</h4>Immune checkpoint inhibitors have improved outcomes in several malignancies, yet durable benefit remains limited in most solid tumors because many lesions exhibit immune-excluded or immune-suppressive tumor microenvironments (TMEs). These resistant states are now understood to arise from coordinated stromal, myeloid, cytokine, vascular, and metabolic programs that prevent effective antitumor immunity and sustain therapeutic failure.<h4>Methods</h4>This review synthesizes recent evidence on the biological architecture of immune-excluded and immune-suppressive TMEs, with particular emphasis on stromal remodeling, cancer-associated fibroblasts, myeloid-cell dominance, cytokine and chemokine networks, vascular dysfunction, metabolic stress, and organ-specific niche effects. We further integrate emerging data from spatial transcriptomics, multiplex imaging, spatial proteomics, and related platforms to evaluate how spatial biomarkers may refine patient stratification and therapeutic decision-making.<h4>Results</h4>Current evidence indicates that resistant TMEs are spatially organized and dynamically evolving ecosystems rather than static histologic phenotypes. CAF/ECM remodeling, suppressive myeloid populations, cytokine circuits, vascular dysfunction, and metabolic stress cooperate to impair T-cell trafficking, infiltration, and effector fitness. Spatially resolved technologies may help refine patient stratification by identifying dominant resistance modules, although prospective clinical validation remains limited.<h4>Conclusion</h4>Immune-excluded and immune-suppressive TMEs represent actionable but heterogeneous resistance states. Future progress will depend on integrating spatially informed biomarker systems, longitudinal profiling, and mechanism-based combination therapies to convert nonresponsive tumors into immunologically permissive niches.