Lymphatic remodelling in the hypoxic tumour microenvironment (TME) is critically involved in the metastasis of cervical squamous cell carcinoma (CSCC); however, its underlying mechanisms remain unclear. Here, we uncovered a novel lymphatic pattern in the hypoxic TME, wherein lymphatic vessels (LVs) are encapsulated by tumour-associated macrophages (TAMs) to form an interconnected network. We describe these aggregates as LVEM (LVs encapsulated by TAMs) considering their advantageous metastatic capacity and active involvement in early lymph node metastasis (LNM). Mechanistic investigations revealed that interleukin-10 (IL-10) derived from hypoxic TAMs adjacent to LVs was a prerequisite for lymphangiogenesis and LVEM formation through its induction of Sp1 upregulation in lymphatic endothelial cells (LECs). Interestingly, Sp1^high LECs promoted the transactivation of C–C motif chemokine ligand 1 (CCL1) to facilitate TAM and tumour cell recruitment, thereby forming a positive feedback loop to strengthen the LVEM formation. Knockdown of Sp1 or blockage of CCL1 abrogated LVEM and consequently attenuated LNM. Notably, CSCC^non-LNM is largely devoid of hypoxic TAMs and the resultant LVEM, which might explain its metastatic delay. These findings identify a novel and efficient metastasis-promoting lymphatic pattern in the hypoxic TME, which might provide new targets for anti-metastasis therapy and prognostic assessment.

低氧肿瘤微环境（TME）中的淋巴重塑与宫颈鳞状细胞癌（CSCC）的转移密切相关；然而，其潜在机制仍不清楚。在这里，我们在缺氧 TME 中发现了一种新的淋巴模式，其中淋巴管 (LV) 被肿瘤相关巨噬细胞 (TAM) 包裹以形成相互连接的网络。考虑到它们有利的转移能力和积极参与早期淋巴结转移 (LNM)，我们将这些聚集体描述为 LVEM（由 TAM 封装的 LV）。机制研究表明，源自与 LV 相邻的缺氧 TAM 的白细胞介素 10 (IL-10) 通过诱导淋巴管内皮细胞 (LEC) 中的 Sp1 上调，是淋巴管生成和 LVEM 形成的先决条件。有趣的是，Sp1^高LEC 促进 C-C 基序趋化因子配体 1 (CCL1) 的反式激活以促进 TAM 和肿瘤细胞募集，从而形成正反馈回路以加强 LVEM 形成。Sp1 的敲低或 CCL1 的阻塞消除了 LVEM，从而减弱了 LNM。值得注意的是，CSCC^{非 LNM}在很大程度上没有低氧 TAM 和由此产生的 LVEM，这可能解释了其转移延迟。这些发现确定了缺氧 TME 中一种新的、有效的促进转移的淋巴管模式，这可能为抗转移治疗和预后评估提供新的靶点。