肺癌是全球癌症相关死亡的主要原因，且预后不良。程序化细胞死亡（PCD）在肺腺癌的肿瘤进展和免疫治疗反应中起着关键作用。利用TCGA，GSE30129，GSE31210，GSE37745，GSE42127，GSE50081，GSE68467，GSE68571和GSE72094数据集，执行了包括10种方法的集成机器学习过程以开发一个预后细胞死亡特征（CDS）。利用各种方法和单细胞分析评估了CDS与肿瘤免疫微环境之间的相关性。进行了qRT-PCR和CCK-8测定以探究中枢基因的生物学功能。Lasso + survivalSVM方法开发的预后CDS被认为是最优的预后模型。CDS在预测LUAD临床结局方面表现稳定且有效，并在TCGA和8个GEO数据集中作为独立的风险因素。CDS的C指数高于临床分期和许多开发的LUAD特征标记。CDS分数低的LUAD患者具有较高的PD1和CTLA4免疫表型得分，较高的TMB得分，较低的TIDE得分和较低的肿瘤逃逸得分，表明免疫治疗效益更好。单细胞分析揭示了上皮细胞和癌相关成纤维细胞之间通过特定配体受体对的强有力和频繁的通信，包括COL1A2-SDC4和COL1A2-SDC1。离体实验显示，在LUAD中SLC7A5上调且SLC7A5的沉默明显抑制了肿瘤细胞增殖。本研究开发了一种新的LUAD CDS。CDS可作为预测LUAD患者预后和免疫治疗效益的指标。版权所有 © 2023. Elsevier Inc. 发表

Lung cancer is the leading cause of cancer-related deaths worldwide with poor prognosis. Programmed cell death (PCD) plays a crucial function in tumor progression and immunotherapy response in lung adenocarcinoma (LUAD).Integrative machine learning procedure including 10 methods was performed to develop a prognostic cell death signature (CDS) using TCGA, GSE30129, GSE31210, GSE37745, GSE42127, GSE50081, GSE68467, GSE68571, and GSE72094 dataset. The correlation between CDS and tumor immune microenvironment was evaluated using various methods and single cell analysis. qRT-PCR and CCK-8 assay were conducted to explore the biological functions of hub gene.The prognostic CDS developed by Lasso + survivalSVM method was regarded as the optimal prognostic model. The CDS had a stable and powerful performance in predicting the clinical outcome of LUAD and served as an independent risk factor in TCGA and 8 GEO datasets. The C-index of CDS was higher than that of clinical stage and many developed signatures for LUAD. LUAD patients with low CDS score had a higher PD1&CTLA4 immunophenoscore, higher TMB score, lower TIDE score and lower tumor escape score, indicating a better immunotherapy benefit. Single cell analysis revealed a strong and frequent communication between epithelial cells and cancer-related fibroblasts by specific ligand-receptor pairs, including COL1A2-SDC4 and COL1A2-SDC1. Vitro experiment showed that SLC7A5 was upregulated in LUAD and knockdown of SLC7A5 obviously suppressed tumor cell proliferation.Our study developed a novel CDS for LUAD. The CDS served as an indicator for predicting the prognosis and immunotherapy benefits of LAUD patients.Copyright © 2023. Published by Elsevier Inc.