Clinical response to immunotherapy is closely associated with the immunosuppressive tumour microenvironment (TME), and influenced by the dynamic interaction between tumour cells and lymphatic endothelial cells (LECs). Here, we show that high levels of miR-142-5p positively correlate with indoleamine 2,3-dioxygenase (IDO) expression in tumour-associated lymphatic vessels in advanced cervical squamous cell carcinoma (CSCC). The miR-142-5p is transferred by CSCC-secreted exosomes into LECs to exhaust CD8⁺ T cells via the up-regulation of lymphatic IDO expression, which was abrogated by an IDO inhibitor. Mechanistically, miR-142-5p directly down-regulates lymphatic AT-rich interactive domain-containing protein 2 (ARID2) expression, inhibits DNA methyltransferase 1 (DNMT1) recruitment to interferon (IFN)-γ promoter, and enhances IFN-γ transcription by suppressing promoter methylation, thereby leading to elevated IDO activity. Furthermore, increased serum exosomal miR-142-5p levels and the consequent IDO activity positively correlate with CSCC progression. In conclusion, exosomes secreted by CSCC cells deliver miR-142-5p to LECs and induce IDO expression via ARID2–DNMT1–IFN-γ signalling to suppress and exhaust CD8⁺ T cells. Our study suggests that LECs act as an integral component of the immune checkpoint(s) in the TME and may serve as a potential new target for CSCC diagnosis and treatment.

免疫治疗的临床反应与免疫抑制性肿瘤微环境（TME）密切相关，并受到肿瘤细胞与淋巴内皮细胞（LEC）之间动态相互作用的影响。在这里，我们发现，在晚期宫颈鳞状细胞癌（CSCC）中，高水平的 miR-142-5p 与肿瘤相关淋巴管中吲哚胺 2,3-双加氧酶（IDO）的表达呈正相关。 miR-142-5p 由 CSCC 分泌的外泌体转移到 LEC 中，通过上调淋巴 IDO 表达来耗尽 CD8 ⁺ T 细胞，而 IDO 抑制剂可消除这种表达。从机制上讲，miR-142-5p 直接下调淋巴管富含 AT 的相互作用结构域蛋白 2 (ARID2) 表达，抑制 DNA 甲基转移酶 1 (DNMT1) 募集到干扰素 (IFN)-γ 启动子，并通过以下方式增强 IFN-γ 转录：抑制启动子甲基化，从而导致 IDO 活性升高。此外，血清外泌体 miR-142-5p 水平升高以及随之而来的 IDO 活性与 CSCC 进展呈正相关。总之，CSCC 细胞分泌的外泌体将 miR-142-5p 递送至 LEC，并通过 ARID2–DNMT1–IFN-γ 信号传导诱导 IDO 表达，从而抑制和耗尽 CD8 ⁺ T 细胞。我们的研究表明，LEC 作为 TME 中免疫检查点的一个组成部分，可能作为 CSCC 诊断和治疗的潜在新靶点。