Spatiotemporal dynamics of tumor-associated neutrophils: bridging the gap between cancer progression and immunotherapy

Neutrophils, traditionally regarded as short-lived first responders of innate immunity, have emerged as pivotal regulators within the tumor microenvironment (TME). Recent advances reveal that tumor-associated neutrophils (TANs) and neutrophil extracellular traps (NETs) exhibit remarkable spatiotemporal heterogeneity, with their phenotypes and functions dynamically evolving across tumor developmental stages and anatomical niches. TANs and NETs display dual and context-dependent roles: they can promote tumor progression via immune suppression, angiogenesis, extracellular matrix remodeling, and metastatic niche formation, yet also exert anti-tumor functions through cytotoxicity and antigen presentation under specific microenvironmental cues. This review systematically dissects the spatial and temporal dynamics of TANs and NETs, emphasizing their molecular regulation by tumor-derived secretomes, chemokine gradients, hypoxia, stromal interactions, and inflammatory signaling networks. We further delineate the bidirectional crosstalk between TANs and other immune or stromal components that contributes to immune evasion and therapy resistance. Beyond mechanistic insights, we highlight emerging therapeutic strategies, ranging from chemokine axis blockade and phenotypic reprogramming to NETs inhibition and clearance, that hold promise for disrupting neutrophil-mediated tumor support. Finally, we advocate for the integration of cutting-edge spatial and single-cell multi-omics, imaging cytometry, and AI-assisted spatial modeling to enable high-resolution mapping of neutrophil dynamics in situ and to guide precision immunotherapy.