背景：针对肿瘤的发展，近期研究发现了一种新的非凋亡型细胞死亡形式，命名为铜诱导的细胞死亡（cuproptosis）。然而，与cuproptosis相关的长链非编码RNA（lncRNA）在肺腺癌（LUAD）的肿瘤免疫形成和个体化治疗优化方面的潜在作用仍不明确。 方法：从癌症基因组图谱（TCGA）数据库下载了LUAD患者的RNA测序和生存数据用于模型训练；利用GSE29013、GSE30219、GSE31210、GSE37745和GSE50081中的LUAD患者进行验证。从前期研究中提取已验证的cuproptosis相关基因。应用Pearson相关性分析选择cuproptosis相关的lncRNA。从肿瘤和正常组织中选择差异表达的cuproptosis相关lncRNA，并对其进行Cox回归和LASSO回归，建立lncRNA签名以预测LUAD的预后。通过Kaplan-Meier估计器、Cox模型、ROC曲线、tAUC、PCA、评分表预测器、决策曲线分析和实时荧光定量PCR进一步验证模型的准确性。检验了该模型与其他调控细胞死亡形式的联系。通过TMB、免疫相关基因、TIDE评估了签名的免疫治疗能力。评估了该签名与抗癌药物敏感性的关系。应用GSEA、免疫浸润分析和功能实验进一步研究了该签名的功能机制以及免疫细胞在签名的预测能力中的作用。 结果：建立了一个由TSPOAP1-AS1、AC107464.3、AC006449.7、LINC00324、COLCA1、HAGLR、MIR4435-2HG和NKILA组成的八个lncRNA签名，并通过在验证队列上的应用证明了其具有预后预测能力。通过实时荧光定量PCR验证了每一个签名基因在真实世界中的差异表达情况。八个lncRNA签名与2321/3681（63.05%）凋亡相关基因、11/20（55.00%）坏死相关基因、34/50（68.00%）火焰病相关基因和222/380（58.42%）铁病相关基因呈正相关。免疫治疗分析表明，我们的签名可能在预测LUAD患者的免疫治疗效果方面有用。通过免疫浸润分析确定了肥大细胞是支持八个lncRNA签名预测能力的关键角色。 结论：本研究确定了与cuproptosis相关的八个lncRNA签名，可能改善LUAD管理策略。该签名可能具备预测LUAD免疫治疗效果的能力。此外，浸润的肥大细胞可能影响该签名的预测能力。 版权所有 © 2023 Ma、Li、Gu、Yang和Qi。

Background: Cuproptosis is a newly discovered non-apoptotic form of cell death that may be related to the development of tumors. Nonetheless, the potential role of cuproptosis-related lncRNAs in tumor immunity formation and patient-tailored treatment optimization of lung adenocarcinoma (LUAD) is still unclear. Methods: RNA sequencing and survival data of LUAD patients were downloaded from The Cancer Genome Atlas (TCGA) database for model training. The patients with LUAD in GSE29013, GSE30219, GSE31210, GSE37745, and GSE50081 were used for validation. The proofed cuproptosis-related genes were extracted from the previous studies. The Pearson correlation was applied to select cuproptosis-related lncRNAs. We chose differentially expressed cuproptosis-related lncRNAs in the tumor and normal tissues and allowed them to go to a Cox regression and a LASSO regression for a lncRNA signature that predicts the LUAD prognosis. Kaplan-Meier estimator, Cox model, ROC, tAUC, PCA, nomogram predictor, decision curve analysis, and real-time PCR were further deployed to confirm the model's accuracy. We examined this model's link to other regulated cell death forms. Applying TMB, immune-related signatures, and TIDE demonstrated the immunotherapeutic capabilities of signatures. We evaluated the relationship of our signature to anticancer drug sensitivity. GSEA, immune infiltration analysis, and function experiments further investigated the functional mechanisms of the signature and the role of immune cells in the prognostic power of the signature. Results: An eight-lncRNA signature (TSPOAP1-AS1, AC107464.3, AC006449.7, LINC00324, COLCA1, HAGLR, MIR4435-2HG, and NKILA) was built and demonstrated owning prognostic power by applied to the validation cohort. Each signature gene was confirmed differentially expressed in the real world by real-time PCR. The eight-lncRNA signature correlated with 2321/3681 (63.05%) apoptosis-related genes, 11/20 (55.00%) necroptosis-related genes, 34/50 (68.00%) pyroptosis-related genes, and 222/380 (58.42%) ferroptosis-related genes. Immunotherapy analysis suggested that our signature may have utility in predicting immunotherapy efficacy in patients with LUAD. Mast cells were identified as key players that support the predicting capacity of the eight-lncRNA signature through the immune infiltrating analysis. Conclusion: In this study, an eight-lncRNA signature linked to cuproptosis was identified, which may improve LUAD management strategies. This signature may possess the ability to predict the effect of LUAD immunotherapy. In addition, infiltrating mast cells may affect the signature's prognostic power.Copyright © 2023 Ma, Li, Gu, Yang and Qi.