Recurrent renal damage and tissue hypoxia sustain NF-κB/STAT3 and HIF-VEGF signaling, while a sustained IFN-γ response enhances antigen presentation while inducing inhibitory checkpoints, promoting a state of “inflammation but constrained.” Single-cell and spatial studies reveal early microenvironment heterogeneity and the chemokine-checkpoint paradox: regions enriched in CXCL9/10 coexist with endothelial inertia, cancer-associated fibroblasts (CAFs)-mediated stromal barriers, and metabolic stress, which collectively exclude functional CD8+T cells. The gene discussed is NFKB1; the disease is cancer.