中性粒细胞胞外陷阱（NET）已被证明可以促进多种肿瘤的转移潜力。我们的研究旨在探讨NETs在宫颈癌（CCa）淋巴结转移（LNM）中的作用和机制，并评估靶向NETs在CCa中的治疗价值。免疫组织化学表明，患有 LNM 的 CCa 患者中性粒细胞浸润和 NET 形成增加，并证实了 CCa 中 S100A7 表达与中性粒细胞浸润之间呈正相关。 NETs 通过与 TLR2 相互作用激活 P38-MAPK/ERK/NFκB 通路来增强 CCa 的迁移能力。用脱氧核糖核酸酶 1 (DNase 1) 消化 NET 或用氯喹抑制 TLR2 可以消除 NET 诱导的 CCa 转移潜力。此外，NETs促进淋巴管生成并增加淋巴管的通透性，从而促进CCa的跨淋巴运动。 CCa 衍生的 S100A7 对中性粒细胞表现出趋化作用，并通过提高 ROS 水平而不是激活中性粒细胞的自噬来促进 NET 的生成。足垫植入的小鼠模型表明，DNase 1 可有效减少 LPS 诱导的小鼠和接种 S100A7 过表达 CCa 细胞的小鼠的 LNM。总之，我们的研究揭示了S100A7的一种新的促癌机制，阐明了NETs在CCa LNM中的关键作用和机制，并表明NETs靶向治疗成为一种有前途的CCa抗转移治疗方法。版权所有©2024作者们。由 Elsevier B.V. 出版。保留所有权利。

Neutrophil extracellular traps (NETs) have been shown to promote the metastatic potential of many kinds of tumors. Our study aimed to investigate the role and mechanisms of NETs in lymph node metastasis (LNM) of cervical cancer (CCa), and evaluated the therapeutic value of targeting NETs in CCa. Immunohistochemistry demonstrated that neutrophil infiltration and NETs formation were increased in CCa patients with LNM, as well as confirming a positive correlation between S100A7 expression and neutrophil infiltration in CCa. NETs enhanced the migratory capability of CCa by activating the P38-MAPK/ERK/NFκB pathway through interaction with TLR2. Digesting NETs with deoxyribonuclease 1 (DNase 1) or inhibiting TLR2 with chloroquine eliminated the NETs-induced metastatic potential of CCa. Additionally, NETs promoted lymphangiogenesis and increased the permeability of lymphatic vessels, thus facilitating translymphatic movement of CCa. CCa-derived S100A7 exhibited a chemotactic effect on neutrophils and promoted NETs generation by elevating ROS levels rather than activating autophagy in neutrophils. The mouse model with footpad implantation illustrated that DNase 1 effectively reduced LNM in LPS-induced mice and in mice seeded with S100A7-overexpressing CCa cells. In conclusion, our study reveals a new tumor-promoting mechanism of S100A7, clarifies the crucial role and mechanism of NETs in LNM of CCa, and indicates that the NETs-targeted therapy emerges as a promising anti-metastasis therapy in CCa.Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.