幼稚 CD4 T 细胞及其分化的对应物在肿瘤免疫微环境中发挥着重要的调节作用，但它们对肺腺癌 (LUAD) 的影响尚未完全了解。我们利用孟德尔随机化来评估幼稚 CD4 T 细胞与 LUAD 之间的因果关系。我们采用改进的单样本基因集富集分析 (ssGSEA) 算法和癌症基因组图谱 (TCGA) 数据库，确定了初始 CD4 T 细胞的浸润水平及其分化亚型，并研究了它们与临床特征的相关性。通过Mantel试验和京都基因与基因组百科全书（KEGG）数据库富集分析确定了T辅助细胞的潜在调控途径。孟德尔随机化分析揭示了幼稚CD4 T细胞对LUAD的抑制作用（错误发现率 < 0.05），这是使用 TCGA 数据库的观察实验证实了这一点。具体而言，2 型辅助 T 细胞在总体生存、无病生存和无进展生存方面表现出对 LUAD 的促进作用 (p<0.05)。此外，调节性 T 细胞在疾病特异性存活方面对 LUAD 表现出保护作用 (p<<0.01)。同时，我们探索了幼稚 CD4 T 细胞分化亚型对 LUAD 的总体影响，揭示了中性粒细胞脱颗粒、MAPK 家族信号通路以及血小板激活、信号传导和聚集等途径的上调。幼稚 CD4 T 细胞及其分化的对应物发挥着至关重要的作用在肿瘤免疫微环境中发挥调节作用，证明其作用具有双向性。因此，阐明其机制并开发新型细胞分化诱导剂将有利于抗癌治疗。© 2024。作者。

Naïve CD4+ T cells and their differentiated counterparts play a significant regulatory role in the tumor immune microenvironment, yet their effects on lung adenocarcinoma (LUAD) are not fully understood.We utilized Mendelian randomization to assess the causal association between naïve CD4+ T cells and LUAD. Employing a modified single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm with The Cancer Genome Atlas (TCGA) database, we determined the infiltration levels of naïve CD4+ T cells and their differentiation subtypes and investigated their correlation with clinical characteristics. Potential regulatory pathways of T helper cells were identified through Mantel tests and Kyoto Encyclopedia of Genes and Genomes (KEGG) database enrichment analysis.Mendelian randomization analysis revealed an inhibitory effect of naïve CD4+ T cells on LUAD (false discovery rate < 0.05), which was corroborated by observational experiments using TCGA database. Specifically, T helper cell type 2 demonstrated a promotive effect on LUAD in terms of overall, disease-free, and progression-free survival (p < 0.05). Moreover, regulatory T cells exhibited a protective effect on LUAD in terms of disease-specific survival (p < 0.01). Concurrently, we explored the overall impact of naïve CD4+ T cell differentiation subtypes on LUAD, revealing upregulation in pathways such as neutrophil degranulation, MAPK family signaling pathways, and platelet activation, signaling, and aggregation.Naïve CD4+ T cells and their differentiated counterparts play essential regulatory roles in the tumor immune microenvironment, demonstrating bidirectionality in their effects.Thus, elucidating the mechanisms and developing novel cell differentiation-inducing agents will benefit anti-cancer therapy.© 2024. The Author(s).