ORIGINAL RESEARCH article
Front. Genet.
Sec. Cancer Genetics and Oncogenomics
Volume 16 - 2025 | doi: 10.3389/fgene.2025.1606111
The Potential Impact of GLS and PDHA1 on Tumor Immunity and Immunotherapy Response in LUSC
Provisionally accepted
- 1Guangzhou University of Chinese Medicine, Guangzhou, China
- 2Boai Hospital of Zhongshan, Zhongshan, China
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Lung squamous cell carcinoma (LUSC) shows heterogeneous responses to immunotherapy. Cuproptosis, a copper-dependent cell death pathway, may modulate the tumor immune microenvironment (TIME). The interplay between glutaminase (GLS) and pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) in cuproptosis-mediated immune-metabolic crosstalk remains uncharacterized in LUSC. This study investigates how GLS/PDHA1 expression shapes TIME and stratifies immunotherapy responsiveness.GLS and PDHA1 were identified as top cuproptosis-linked genes via correlation with ESTIMATE immune scores. Consensus clustering stratified 501 TCGA-LUSC patients by GLS/PDHA1 expression. Immune infiltration was quantified using ESTIMATE, CIBERSORT, and ssGSEA. Pathway enrichment was analyzed via GSEA and WGCNA. Single-cell RNA sequencing (scRNA-seq) of 17,050 cells from two LUSC patients revealed cellular gene expression dynamics. Findings were validated in four independent GEO cohorts (n=278).Two subtypes emerged: Cluster 1 (low GLS/high PDHA1) and Cluster 2 (high GLS/low PDHA1). Cluster 2 exhibited enhanced immune infiltration, elevated immune checkpoint expression (e.g., PD-1, CTLA-4), and enriched T-cell activation pathways. Validation confirmed Cluster 2’s conserved "immune-hot" phenotype with higher stromal scores, reduced tumor purity, and expanded activated immune subsets. scRNA-seq pinpointed malignant epithelial cells as hubs of divergent GLS/PDHA1 expression (high GLS/low PDHA1), orchestrating cuproptosis-immunometabolic crosstalk via cytokine signaling.GLS and PDHA1 expression stratifies LUSC into distinct immune phenotypes. Cluster 2’s high-GLS/low-PDHA1 signature correlates with an inflamed TIME and superior immunotherapy response potential. Targeting cuproptosis may convert "cold" to "hot" tumors, advancing precision immunotherapy in LUSC.
Keywords: lung squamous cell carcinoma (LUSC), cuproptosis, GLS, PDHA1, immune microenvironment, Immunotherapy, metabolic-immune crosstalk
Received: 04 Apr 2025; Accepted: 11 Aug 2025.
Copyright: © 2025 Ling, JIAHUI and XIAOHAO. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: LING XIAOHAO, Guangzhou University of Chinese Medicine, Guangzhou, China
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