Tumor-associated neutrophils in lung adenocarcinoma: from mechanisms to therapeutic targeting

Lung adenocarcinoma (LUAD) is the predominant subtype of non-small cell lung cancer (NSCLC), characterized by a complex tumor microenvironment (TME) where tumor-associated neutrophils (TANs) exert dual functions-a concept now well-established in broader NSCLC and pan-cancer studies. Despite the advances in immune checkpoint inhibitors (ICIs), primary and acquired resistance remain major obstacles. This review comprehensively dissects the regulatory network of TANs in LUAD, including their recruitment via the CXCR1/CXCR2 axis, polarization towards anti-tumorigenic N1 or pro-tumorigenic N2 phenotypes under the influence of TGF-β and IFN-γ, and the formation of neutrophil extracellular traps (NETs). We highlight the dual functions of TANs and NETs in both tumor promotion (immunosuppression, angiogenesis, metastasis) and tumor suppression (direct cytotoxicity, antigen presentation). Furthermore, we evaluate current therapeutic strategies targeting TANs, such as CXCR1/2 inhibitors (SX-682, Navarixin), PAD4 inhibitors (Cl-amidine), NET-degrading enzymes (DNase I), TGF-β inhibitors (Galunisertib), and myeloid modulators, with a focus on LUAD-specific preclinical and clinical evidence. Major challenges, including off-target toxicity, infection risk, and the lack of predictive biomarkers, are discussed. By bridging mechanistic insights with translational opportunities, this review provides a framework for developing neutrophil-targeted combination therapies to overcome immunotherapy resistance in LUAD.