Neutrophil-based immunotherapy: A metabolic lens on mechanisms and therapeutic implications

Tumor-associated neutrophils (TANs) serve as pivotal immune modulators in the tumor microenvironment and exert profound, context-dependent effects on tumor immunity, yet their metabolic features and functional implications remain insufficiently explored.

Throughout their lifecycle, neutrophils continuously sense and adapt to shifting microenvironments, maintaining survival and functional homeostasis through metabolic reprogramming. As key hubs of the tumor metabolic network, TANs exhibit pronounced metabolic plasticity and heterogeneity. Whether active or passive, TAN metabolic reprogramming critically contributes to immune evasion via multiple mechanisms, including regulation of immune mediator expression and intercellular metabolite crosstalk. Current research focuses on strategies that induce durable TAN metabolic reprogramming while overcoming inherent limitations, aiming to establish an efficient and safe TAN-directed immunotherapeutic framework. In this review, we systematically summarize recent advances in TAN metabolic reprogramming, emphasizing its intrinsic link to immunological phenotypes and spatiotemporal heterogeneity. We also propose a TAN metabolic classification framework (4-Tier TAN-MetaC) and provide a comprehensive overview of translational opportunities, bottlenecks, and actionable future directions for TAN metabolism-targeted immunotherapies.

Overall, TAN metabolic reprogramming represents a central driver of tumor immune evasion and a clinically actionable metabolic vulnerability for cancer immunotherapy.

Tumour-associated neutrophil (TAN) metabolic reprogramming is tightly linked to their immunosuppressive functions. Spatiotemporal metabolic heterogeneity shapes TAN-mediated tumour immunity. A metabolism-based TAN stratification model unifies cross-study frameworks. TAN metabolism-targeted immunotherapy holds promise for improving patient prognosis.