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Background <p>Aldolase A (ALDOA), a key glycolytic enzyme, has been implicated in tumor progression and metabolic reprogramming across multiple cancers [<CitationRef CitationID="CR1">1</CitationRef>]. However, its role in lung squamous cell carcinoma (LUSC) remains largely unexplored. Recent studies suggest that ALDOA may influence the tumor immune microenvironment, particularly through its association with macrophages [<CitationRef CitationID="CR2">2</CitationRef>, <CitationRef CitationID="CR3">3</CitationRef>]. This study aims to investigate the prognostic value of ALDOA in LUSC and its role in macrophage-mediated immune suppression.</p> Methods <p>We conducted a comprehensive pan-cancer analysis to evaluate ALDOA expression, genomic alterations, and prognostic relevance across different cancer types. In LUSC, we validated its prognostic value using immunohistochemical (IHC) staining and independent patient cohorts. Immune infiltration was assessed using multiple bioinformatics algorithms and single-cell RNA sequencing (scRNA-seq) from the TISCH2 database. Spatial transcriptomics and immunofluorescence (IF) staining were performed to determine ALDOA’s co-localization with CD68 + macrophages in LUSC tissues. Functional enrichment and drug sensitivity analyses were conducted to explore ALDOA’s role in tumor progression and therapeutic resistance.</p> Results <p>ALDOA was significantly overexpressed in multiple cancers, with LUSC showing one of the highest expression levels. Elevated ALDOA expression was strongly correlated with poor overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) in LUSC patients. Copy number variations and promoter hypomethylation were identified as potential mechanisms driving ALDOA overexpression. ALDOA-high tumors exhibited increased M0 macrophage and reduced CD8 + T-cell infiltration, suggesting a role in immune suppression and evasion. Spatial transcriptomic and immunofluorescence analyses confirmed the co-localization of ALDOA with CD68 + tumor-associated macrophages (TAMs). Additionally, ALDOA-high tumors demonstrated increased resistance to multiple chemotherapeutic agents and EGFR-TKIs, highlighting its potential as a predictive biomarker for drug response.</p> Conclusion <p>Our findings establish ALDOA as a robust prognostic biomarker and a key regulator of macrophage-mediated immune suppression in LUSC. Its involvement in tumor metabolism, immune evasion, and therapy resistance suggests that targeting ALDOA could enhance both metabolic inhibition strategies and immune checkpoint blockade therapies. Future research should focus on mechanistic studies and therapeutic interventions targeting ALDOA to improve treatment outcomes in LUSC.</p>

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Aldolase a in pan-cancer and lung squamous cell carcinoma: prognostic value and macrophage-driven immune suppression unveiled by multi-omics and cohort validation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月14日

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  • Ying Ji,
  • Xincheng Li,
  • Xihao Shen,
  • Xiumei Hu,
  • Yujing Du,
  • Bin Hu,
  • Wei Wang,
  • Fanjie Meng

摘要

Background

Aldolase A (ALDOA), a key glycolytic enzyme, has been implicated in tumor progression and metabolic reprogramming across multiple cancers [1]. However, its role in lung squamous cell carcinoma (LUSC) remains largely unexplored. Recent studies suggest that ALDOA may influence the tumor immune microenvironment, particularly through its association with macrophages [2, 3]. This study aims to investigate the prognostic value of ALDOA in LUSC and its role in macrophage-mediated immune suppression.

Methods

We conducted a comprehensive pan-cancer analysis to evaluate ALDOA expression, genomic alterations, and prognostic relevance across different cancer types. In LUSC, we validated its prognostic value using immunohistochemical (IHC) staining and independent patient cohorts. Immune infiltration was assessed using multiple bioinformatics algorithms and single-cell RNA sequencing (scRNA-seq) from the TISCH2 database. Spatial transcriptomics and immunofluorescence (IF) staining were performed to determine ALDOA’s co-localization with CD68 + macrophages in LUSC tissues. Functional enrichment and drug sensitivity analyses were conducted to explore ALDOA’s role in tumor progression and therapeutic resistance.

Results

ALDOA was significantly overexpressed in multiple cancers, with LUSC showing one of the highest expression levels. Elevated ALDOA expression was strongly correlated with poor overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) in LUSC patients. Copy number variations and promoter hypomethylation were identified as potential mechanisms driving ALDOA overexpression. ALDOA-high tumors exhibited increased M0 macrophage and reduced CD8 + T-cell infiltration, suggesting a role in immune suppression and evasion. Spatial transcriptomic and immunofluorescence analyses confirmed the co-localization of ALDOA with CD68 + tumor-associated macrophages (TAMs). Additionally, ALDOA-high tumors demonstrated increased resistance to multiple chemotherapeutic agents and EGFR-TKIs, highlighting its potential as a predictive biomarker for drug response.

Conclusion

Our findings establish ALDOA as a robust prognostic biomarker and a key regulator of macrophage-mediated immune suppression in LUSC. Its involvement in tumor metabolism, immune evasion, and therapy resistance suggests that targeting ALDOA could enhance both metabolic inhibition strategies and immune checkpoint blockade therapies. Future research should focus on mechanistic studies and therapeutic interventions targeting ALDOA to improve treatment outcomes in LUSC.