Bidirectional role of neutrophils in lung cancer: Mechanisms and therapeutic implications

Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) being the predominant subtype. Despite the availability of traditional treatments such as radiation therapy, chemotherapy, and surgery, as well as emerging immunotherapies, the five-year survival rate and prognosis remain suboptimal. Tumor-associated neutrophils (TANs) are the most abundant immune cells in the tumor microenvironment (TME) of lung cancer, and understanding their role in cancer therapy is highly important. This review comprehensively discusses the dual role of TANs in lung cancer progression. First, we examined the recruitment, classification, and single-cell heterogeneity of TANs, highlighting the distinct molecular expression and functions across subpopulations. Mechanistically, TANs influence tumor behavior through direct cellcell interactions and cytokine production. Additionally, neutrophils engage with other cells in the TME via metabolic reprogramming, programmed cell death, epigenetic modifications, and vesicle secretion. To date, no studies have systematically summarized and connected these mechanisms. Finally, we summarize the clinical applications and prospects of TANs in lung cancer, including their potential role in assisting in diagnosis, predicting prognosis, and targeting neutrophils to increase the efficacy of radiation, chemotherapy, and immunotherapy. We hope that this review provides insights for future research aimed at improving lung cancer prognosis through the targeting of TANs.