虽然大多数子宫内膜癌（EC）患者拥有良好的预后，但转移性和复发性EC的总体生存率（OS）却几乎无法通过当前的化疗放疗得到改善。我们旨在揭示肿瘤微环境的免疫浸润特征，以阐明EC进展的潜在机制并指导临床决策。在癌症基因组图谱（TCGA）队列中，Kaplan-Meier生存曲线证实，Treg和CD8 T细胞是EC OS的预后保护因子（P<0.05）。加权基因共表达网络分析确定了2个基因模块与Treg和CD8 T细胞浸润密切相关。我们以7:3的比例随机将TCGA EC队列分为训练组和测试组。通过单变量分析、最小绝对值收缩与选择操作和多元Cox回归建立了一个免疫相关的预后风险指数（IRPRI），其中包括NR3C1、E2F1、OTOG、TTK、PPP1R16B和FOXP3，曲线下面积>0.67。多组学分析显示IRPRI组之间存在明显的临床、免疫和突变特征。细胞增殖和DNA损伤修复相关途径被激活，而免疫相关途径被抑制。此外，IRPRI高组的患者具有较低的肿瘤突变负荷、程序性死亡配体1表达及肿瘤免疫功能失调和排斥得分，表明对免疫检查点抑制剂治疗的反应较差（P<0.05），这也在TCGA测试组和独立队列GSE78200、GSE115821和GSE168204中得以验证。此外，IRPRI低组中BRCA1、BRCA2和同源重组修复的基因的较高突变频率预测对PARP抑制剂的良好反应。最后，我们制作并验证一个结合IRPRI组和预后相关临床病理因素的计分表，用于EC OS预测，具有很好的区分度和校准。版权所有©2023 Wolters Kluwer Health，Inc.保留所有权利。

Although most endometrial cancer (EC) patients have a favorable prognosis, the overall survival (OS) of metastatic and recurrent EC could hardly be improved by the current chemoradiotherapy. We aimed to reveal the tumor microenvironment immune infiltration characteristics to elucidate the underlying mechanism of EC progression and guide clinical decisions. In the Cancer Genome Atlas (TCGA) cohort, Kaplan-Meier survival curves confirmed Tregs and CD8 T cells were prognosis-protective factors in OS of EC (P<0.05). Weighted gene coexpression network analysis identified 2 gene modules closely correlated with Tregs and CD8 T-cell infiltration. We randomly split the TCGA EC cohort into the training and testing cohorts at a ratio of 7:3. An immune-related prognosis risk index (IRPRI), including NR3C1, E2F1, OTOG, TTK, PPP1R16B, and FOXP3, was established by univariate, Least Absolute Shrinkage and Selection Operator, and multivariate Cox regression with area under the curve >0.67. Distinct clinical, immune, and mutation characteristics existed between IRPRI groups by multiomics analysis. Cell proliferation and DNA damage repair-related pathways were activated, and immune-related pathways were inactivated in the IRPRI-high group. Furthermore, patients in the IRPRI-high group had lower tumor mutation burden, programmed death-ligand 1 expression, and Tumor Immune Dysfunction and Exclusion scores, indicating a poor response to immune checkpoint inhibitors therapy (P<0.05), which was also validated in the TCGA testing cohort and independent cohorts, GSE78200, GSE115821, and GSE168204. Also, the higher mutation frequencies of BRCA1, BRCA2, and genes enrolled in homologous recombination repair in the IRPRI-low group predicted a good response to PARP inhibitors. Finally, a nomogram integrating the IRPRI group and prognosis significant clinicopathological factors for EC OS prediction was developed and validated with good discrimination and calibration.Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.