Harnessing neutrophil plasticity: From mechanistic insights to oncology therapeutics

Neutrophils are dynamic regulators of cancer progression rather than short-lived bystanders. Within the tumor microenvironment (TME), tumor-associated neutrophils (TANs) adopt heterogeneous, context-dependent states that extend far beyond the conventional N1/N2 dichotomy. Recent single-cell and spatial transcriptomic insights reveal that cytokine, stromal, metabolic, and epigenetic cues orchestrate this remarkable TAN plasticity. Once activated, TAN-derived proteases, reactive oxygen species, and neutrophil extracellular traps (NETs) drive angiogenesis, immune evasion, metastasis, and therapy resistance. Conversely, specific TAN subpopulations can directly kill tumor cells, present antigens, and synergize with adaptive immunity. This review synthesizes recent breakthroughs in TAN recruitment, heterogeneity, metabolic and epigenetic reprogramming, and cellular crosstalk. Furthermore, we evaluate therapeutic strategies targeting molecular signaling and NET formation, alongside emerging approaches to reprogram or engineer neutrophils, such as chimeric antigen receptor-engineered neutrophils (CAR-Ns). Finally, we address current barriers to clinical translation and outline how to achieve context-dependent modulation of neutrophil states to preserve essential host defenses during TAN-targeted oncology therapies.