Metabolic Reprogramming Regulates Neutrophil Plasticity: From Acute Infection to Tumour Immunosuppression

ABSTRACT Neutrophils are highly adaptable innate immune cells whose functions extend beyond antimicrobial defence to include regulation of chronic inflammation, tumour progression and tissue injury. Although traditionally considered glycolysis‐dependent effector cells, emerging evidence reveals substantial metabolic plasticity that enables neutrophils to adapt to diverse microenvironmental pressures. Metabolic programmes involving carbohydrate utilisation, mitochondrial regulation, lipid metabolism, amino‐acid‐derived metabolites and redox control dynamically shape neutrophil migration, antimicrobial activity, survival, extracellular trap formation and immunoregulatory functions. However, the biological consequences of metabolic reprogramming are highly context dependent and the same pathway may support protective host defence in acute infection while promoting pathological inflammation or immunosuppression in chronic disease. Here, we develop a three‐axis comparative framework based on temporal mode of metabolic reprogramming, granulocytic population identity and evidence level to examine neutrophil metabolism across acute infection, cancer and chronic inflammatory or metabolic disorders. This framework distinguishes transient metabolic adaptation in conventional neutrophils from sustained metabolic states associated with tumour‐associated neutrophils and polymorphonuclear myeloid‐derived suppressor cells, while separating direct human neutrophil evidence from broader myeloid or preclinical observations. We discuss how metabolic pathways, including glycolysis, mitochondrial signalling, lipid handling, itaconate biology and ferroptosis‐related mechanisms, are differentially engaged according to cellular state and tissue context. Finally, we evaluate emerging therapeutic strategies targeting neutrophil metabolism and highlight key translational challenges, including target specificity, preservation of antimicrobial competence, delivery strategies and patient selection. By integrating metabolic mechanisms with cellular identity and evidence strength, this review provides a framework for understanding how neutrophil metabolic plasticity contributes to immune protection and disease progression and identifies principles for developing context‐selective therapeutic approaches.