Metabolic-Immune Coupling in Urologic Cancers: Macrophage Reprogramming as a Therapeutic Nexus

Therapeutic responsiveness in urologic cancers is gated by metabolic-immune coupling that conditions tumor-associated macrophages (TAMs). Myeloid-dominated "cold" ecosystems blunt antigen handling, phagocytosis, and trafficking, limiting the benefit of immune-checkpoint inhibitors (ICIs). This review focuses on three high-value axes that shape TAM state and niche: the lactate-pH / hypoxia-HIF-VEGF axis that enforces acidic, adenosinergic suppression and angiogenic programs; lipid rafts axis that stabilizes inhibitory hubs (e.g., PI3K-AKT/TREM2) and skews phagocytosis/antigen presentation; and ferroptosis-redox axis control that sets inflammatory versus tolerogenic set-points. The review further outlines pharmacodynamic anchors-hyperpolarized ¹³C-pyruvate MRI (k_PL), soluble ANGPT2, and spatial NT5E/ADORA2A modules-to operationalize a bench-to-biomarker-to-bedside loop using organoid-immune co-cultures, humanized/xenograft systems, and ex vivo tumor slices. This framework prioritizes adaptive enrichment for glycolysis- or adenosine-high tumors, rational timing/sequencing with ICIs, and avoidance of global myelosuppression. Collectively, metabolism-informed TAM re-education offers a route to convert myeloid-dominated "cold" ecosystems into treatment-responsive states across urologic cancers.