中性粒细胞胞外诱捕网在非小细胞肺癌转移中的双重作用：机制、靶点及治疗前景

The Dual Role of Neutrophil Extracellular Traps in the Metastasis of Non-Small Cell Lung Cancer: Mechanisms, Targets, and Therapeutic Prospects

摘要: 肺癌包括小细胞肺癌和非小细胞肺癌，因其高死亡率和发病率，是全球癌症相关死亡率的主要原因。中性粒细胞胞外诱捕网是来源于活化的中性粒细胞释放的由解集缩染色质纤维及抗菌颗粒蛋白组成的网状结构。中性粒细胞胞外诱捕网可通过捕获并直接杀伤肿瘤细胞限制早期转移，增强抗肿瘤免疫应答发挥抑癌作用。但是，越来越多研究表明中性粒细胞胞外诱捕网可通过STING等通路激活炎症反应，促进IL-8、IL-1β和TNF-α等细胞因子的释放，增强肿瘤细胞的存活和扩散能力。通过招募髓源性抑制细胞、肿瘤相关巨噬细胞和调节性T细胞等，中性粒细胞胞外诱捕网可抑制CD8+ T细胞和NK细胞的抗肿瘤活性。此外，中性粒细胞胞外诱捕网还可通过细胞外基质重塑促进休眠的播散性肿瘤细胞增殖。这种双重作用机制复杂且高度依赖肿瘤微环境。中性粒细胞胞外诱捕网在非小细胞肺癌转移中的关键作用使其成为极具潜力的治疗靶点，目前针对中性粒细胞胞外诱捕网的干预策略主要有中性粒细胞胞外诱捕网形成抑制(PAD4抑制剂)，中性粒细胞胞外诱捕网降解(如DNase I)等。本文综述中性粒细胞胞外诱捕网在非小细胞肺癌转移中的关键机制，为中性粒细胞介导的肿瘤动力学的新治疗策略提供基础。

Abstract: Lung cancer, encompassing small cell lung cancer and non-small cell lung cancer, is among the primary causes of cancer-related deaths globally. Neutrophil extracellular traps are reticular structures consisting of decondensed chromatin fibers and antimicrobial granule proteins, released by activated neutrophils. Neutrophil extracellular traps exert antitumor effects by inhibiting early metastasis through the direct capture and killing of tumor cells, while also enhancing antitumor immune responses. However, a growing body of research indicates that neutrophil extracellular traps activate inflammatory pathways, such as STING, which promotes the release of cytokines like IL-8, IL-1β, and TNF-α, thereby enhancing tumor cell survival and proliferation. Additionally, they recruit myeloid suppressor cells, tumor-associated macrophages, and regulatory T cells, while suppressing the antitumor activity of CD8+ T cells and NK cells. Furthermore, neutrophil extracellular traps facilitate tumor cell proliferation by remodeling the extracellular matrix. This dual-action mechanism is complex and highly dependent on the tumor microenvironment. The crucial role of the neutrophil extracellular trap in non-small cell lung cancer metastasis makes it a highly promising therapeutic target. Current intervention strategies targeting the neutrophil extracellular trap mainly include inhibition of neutrophil extracellular trap formation (PAD4 inhibitors) and neutrophil extracellular trap degradation (such as DNase I). This article reviews the key mechanisms of the neutrophil extracellular trap in non-small cell lung cancer metastasis, providing a foundation for novel therapeutic strategies based on neutrophil-mediated tumor dynamics.