子宫颈癌是一种常见的妇科肿瘤。越来越多的证据表明缺氧在肿瘤进展和免疫中发挥重要作用。然而，目前尚无研究探讨子宫颈癌的缺氧状况。在本研究中，我们使用分层聚类法根据先前描述的缺氧相关基因，从The Cancer Genome Atlas数据集中确定了三种子宫颈癌样本的缺氧亚型。这些亚型在总体生存时间、缺氧特征、基因组学和免疫学特征上存在明显差异。我们还通过主成分分析生成了一个缩减维度的缺氧评分（hypoxia score）。通过GSE44001验证，缺氧评分被证明是一种有效的预后生物标志物，并与免疫治疗反应相关。此外，结合单细胞RNA测序(scRNA-seq)和实验，我们确定S100A2是缺氧诱导的免疫抑制因子，并调控PD-L1的表达。S100A2还作为一个促进子宫颈癌细胞增殖和迁移的癌基因。这些发现描绘了一种基于缺氧的新分类，并确定S100A2作为子宫颈癌的潜在治疗靶点，从而推动了对免疫治疗耐药机制和子宫颈癌遗传标志的理解。© 2023年作者，独家许可给生殖调查协会。

Cervical cancer is a common gynecological oncology. Growing evidence indicates hypoxia plays an important role in tumor progression and immunity. However, no study has examined the hypoxia landscape in cervical cancer. In this study, using hierarchical clustering, we identified three hypoxia subtypes in cervical cancer samples from The Cancer Genome Atlas dataset according to formerly described hypoxia-related genes. The overall survival time, hypoxic features, genomics, and immunological characteristics of these subtypes existed distinct differences. We also created a hypoxia score by principle component analysis for dimension reduction. The hypoxiaScore was an effective prognostic biomarker validated by GSE44001 and was associated with immunotherapy response. Furthermore, combined with single-cell RNA-sequence (scRNA-seq) and experiments, S100A2 was identified as an immunosuppressive factor induced by hypoxia and regulated expression of PD-L1. S100A2 also served as an oncogene promoting the proliferation and migration of cervical cancer cells. These findings depicted a new hypoxia-based classification and identified S100A2 as a potential therapeutic target for cervical cancer, thereby advancing the understanding of immunotherapy resistance mechanisms and cervical cancer genetic markers.© 2023. The Author(s), under exclusive licence to Society for Reproductive Investigation.