The tumor microenvironment (TME) influences the occurrence and progression of tumors, and hypoxia is an important characteristic of the TME. The expression of programmed death 1 (PD1)/programmed death-ligand 1 (PDL1), cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), and other immune checkpoints in hypoxic malignant tumors is often significantly increased, and is associated with poor prognosis. The application of immune checkpoint inhibitors (ICIs) for treating lung cancer, urothelial carcinoma, and gynecological tumors has achieved encouraging efficacy; however, the rate of efficacy of ICI single-drug treatment is only about 20%. In the present review, we discuss the possible mechanisms by which the hypoxic TME regulates immune checkpoints. By activating hypoxia-inducible factor-1α (HIF-1α), regulating the adenosine (Ado)-A2aR pathway, regulating the glycolytic pathway, and driving epithelial-mesenchymal transition (EMT) and other biological pathways, hypoxia regulates the expression levels of CTLA4, PD1, PDL1, CD47, lymphocyte activation gene 3 (LAG3), T-cell immunoglobulin and mucin domain 3 (TIM3), and other immune checkpoints, which interfere with the immune effector cell anti-tumor response and provide convenient conditions for tumors to escape immune surveillance. The combination of HIF-1α inhibitors, Ado-inhibiting tumor immune microenvironment regulatory drugs, and other drugs with ICIs has good efficacy in both preclinical studies and phase I-II clinical studies. Exploring the effects of TME hypoxia on the expression of immune checkpoints and the function of infiltrating immune cells has greatly clarified the relationship between the hypoxic TME and immune escape, which is of great significance for the development of new drugs and the search for predictive markers of the efficacy of immunotherapy for treating malignant tumors. In the future, combination therapy with hypoxia pathway inhibitors and ICIs may be an effective anti-tumor treatment strategy.

中文翻译：

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低氧肿瘤微环境对免疫检查点的调节

肿瘤微环境（TME）影响肿瘤的发生和发展，缺氧是TME的重要特征。低氧恶性肿瘤中程序性死亡1（PD1）/程序性死亡配体1（PDL1），细胞毒性T淋巴细胞相关抗原4（CTLA4）和其他免疫检查点的表达通常显着增加，并且与不良预后相关。免疫检查点抑制剂（ICIs）在治疗肺癌，尿路上皮癌和妇科肿瘤中的应用取得了令人鼓舞的疗效。但是，ICI单药治疗的疗效率仅为20％左右。在本综述中，我们讨论了低氧TME调节免疫检查点的可能机制。通过激活缺氧诱导因子-1α（HIF-1α），调节腺苷（Ado）-A2aR途径，缺氧调节糖酵解途径并驱动上皮-间质转化（EMT）和其他生物途径，从而调节CTLA4，PD1，PDL1，CD47，淋巴细胞活化基因3（LAG3），T细胞免疫球蛋白和粘蛋白结构域3（ TIM3）和其他免疫检查点，它们干扰免疫效应细胞的抗肿瘤反应，并为肿瘤逃避免疫监视提供了便利条件。HIF-1α抑制剂，抑制Ado的肿瘤免疫微环境调节药物以及其他具有ICI的药物的组合在临床前研究和I-II期临床研究中均具有良好的疗效。探索TME缺氧对免疫检查点表达和浸润性免疫细胞功能的影响，极大地阐明了低氧TME与免疫逃逸之间的关系，这对于开发新药以及寻找免疫疗法治疗恶性肿瘤疗效的预测指标具有重要意义。将来，与缺氧途径抑制剂和ICIs联合治疗可能是一种有效的抗肿瘤治疗策略。