The potential impact of GLS and PDHA1 on tumor immunity and immunotherapy response in LUSC.

IF 2.8 3区生物学 Q2 GENETICS & HEREDITY

Frontiers in Genetics Pub Date : 2025-09-19 eCollection Date: 2025-01-01 DOI:10.3389/fgene.2025.1606111

Tianhe Ling, Jiahui Wu, Ling Xiaohao

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引用次数: 0

Abstract

Background: Lung squamous cell carcinoma (LUSC), a therapeutically challenging non-small cell lung cancer (NSCLC) subtype with a poor prognosis, exhibits heterogeneous responses to immunotherapy. Cuproptosis, a recently discovered regulated cell death pathway, has been hypothesised to modulate the tumour immune microenvironment (TIME). Despite the well-established role of PDHA1 as a metabolic regulator, the specific mechanisms by which it interacts with GLS in cuproptosis-mediated immune-metabolic crosstalk remain to be elucidated in LUSC. The present study investigates the manner in which GLS/PDHA1 expression patterns influence TIME composition and contribute to the stratification of immunotherapy responsiveness.

Methods: It was determined that GLS and PDHA1 were the most significant copper oxidation-related genes, due to their highest absolute correlation with the ESTIMATE immune score. A consensus clustering analysis was conducted on a cohort of 501 TCGA-LUSC patients, with the objective of stratifying patients based on GLS/PDHA1 expression levels. Quantitative analysis of immune infiltration was performed using ESTIMATE, CIBERSORT, and ssGSEA methods. The pathway enrichment analysis was conducted using GSEA and WGCNA. A detailed analysis of 17,050 single-cell RNA sequencing (scRNA-seq) data from two LUSC patients was conducted, which revealed unique gene expression patterns. The validity of these findings was confirmed through the integration of four independent GEO cohorts (GSE181043/37745/43580/115457; n = 278).

Results: Consensus clustering delineated two subtypes:Cluster 1 (low GLS/high PDHA1) and Cluster 2 (high GLS/low PDHA1). Cluster two showed enhanced immune infiltration, characterized by: Elevated immune checkpoint expression and Enriched T-cell activation pathways. Validation across four GEO cohorts confirmed Cluster two conserved immune-hot phenotypewith elevated ESTIMATE stromal scores, reduced tumor purity, and activated immune subsets. scRNA-seq identified malignant epithelial cells as the hub of divergent GLS/PDHA1 expression (high GLS/low PDHA1), orchestrating cuproptosis-immunometabolic crosstalk.

Conclusion: GLS and PDHA1 have been proposed as potential prognostic markers for immunotherapy. Targeting cuproptosis has the potential to convert immunologically cold to hot tumours, thereby advancing precision immunotherapy.

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GLS和PDHA1对LUSC肿瘤免疫和免疫治疗反应的潜在影响。

背景：肺鳞状细胞癌（LUSC）是一种具有治疗挑战性的非小细胞肺癌（NSCLC）亚型，预后较差，对免疫治疗表现出异质反应。cuprotosis是最近发现的一种受调节的细胞死亡途径，被认为可以调节肿瘤免疫微环境（TIME）。尽管PDHA1作为代谢调节因子的作用已得到证实，但在LUSC中，PDHA1与GLS在铜中毒介导的免疫代谢串扰中相互作用的具体机制仍有待阐明。本研究探讨了GLS/PDHA1表达模式影响TIME组成和促进免疫治疗反应性分层的方式。方法：GLS和PDHA1是最显著的铜氧化相关基因，与ESTIMATE免疫评分的绝对相关性最高。对501例TCGA-LUSC患者进行共识聚类分析，目的是根据GLS/PDHA1表达水平对患者进行分层。采用ESTIMATE、CIBERSORT和ssGSEA方法对免疫浸润进行定量分析。利用GSEA和WGCNA进行途径富集分析。对来自2例LUSC患者的17050个单细胞RNA测序（scRNA-seq）数据进行了详细分析，揭示了独特的基因表达模式。通过整合四个独立的GEO队列（GSE181043/37745/43580/115457; n = 278），证实了这些发现的有效性。结果：一致聚类描述了两个亚型：集群1（低GLS/高PDHA1）和集群2（高GLS/低PDHA1）。集群二显示免疫浸润增强，其特征是免疫检查点表达升高和t细胞激活途径富集。四个GEO队列的验证证实了第二簇保守的免疫热表型，具有升高的ESTIMATE间质评分，降低的肿瘤纯度和激活的免疫亚群。scRNA-seq鉴定出恶性上皮细胞是GLS/PDHA1表达发散的中枢（高GLS/低PDHA1），协调cuprotysis -免疫代谢串扰。结论：GLS和PDHA1可作为免疫治疗的潜在预后指标。靶向cuprotosis有可能将免疫冷肿瘤转化为热肿瘤，从而推进精确的免疫治疗。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Frontiers in Genetics Biochemistry, Genetics and Molecular Biology-Molecular Medicine

CiteScore

5.50

自引率

8.10%

发文量

3491

审稿时长

14 weeks

期刊介绍： Frontiers in Genetics publishes rigorously peer-reviewed research on genes and genomes relating to all the domains of life, from humans to plants to livestock and other model organisms. Led by an outstanding Editorial Board of the world’s leading experts, this multidisciplinary, open-access journal is at the forefront of communicating cutting-edge research to researchers, academics, clinicians, policy makers and the public. The study of inheritance and the impact of the genome on various biological processes is well documented. However, the majority of discoveries are still to come. A new era is seeing major developments in the function and variability of the genome, the use of genetic and genomic tools and the analysis of the genetic basis of various biological phenomena.