Dynamic Metabolic States in TNBC: Orchestrating Spatiotemporal Adaptation and Therapy.

Triple-negative breast cancer (TNBC) is characterized by marked metabolic plasticity, spatial heterogeneity, and therapy-induced adaptive remodeling. However, TNBC metabolism is often discussed as isolated pathways, making it difficult to link metabolic rewiring to immune exclusion, drug-tolerant persister cells, and treatment windows. Here, we propose a functional metabolic operating-state framework to organize recurrent adaptive programs in TNBC. Importantly, the S1-S5 framework is not a clinically validated subtype classification, but a set of coexisting and reversible operating states shaped by microenvironmental and therapeutic pressures. S1 represents a glycolysis-lactate/acidosis barrier; S2 denotes fatty acid oxidation (FAO)/oxidative phosphorylation (OXPHOS)-supported persister-like survival; S3 reflects NADPH and one-carbon metabolism-mediated reductive defense; S4 captures lipogenesis, cholesterol metabolism, and membrane remodeling; and S5 represents a ferroptosis tipping window emerging when redox and lipid-peroxide defenses fail. We further highlight flux-valve nodes that redirect carbon, nitrogen, lipid, and redox allocation, thereby biasing transitions among these states. Integrating evidence from spatial omics, metabolic imaging, tumor immunology, and therapeutic studies, we discuss how metabolic isozones reinforce immune suppression and how staged interventions may exploit state-specific vulnerabilities. This framework is intended to generate monitorable and falsifiable decision hypotheses for biomarker development, combination therapy design, and future prospective validation in TNBC.