Multi‐Omics Analysis of TYMS as a Prognostic Biomarker and Therapeutic Target for Lung Adenocarcinoma

ABSTRACT Lung adenocarcinoma (LUAD) is a predominant form of lung cancer with poor prognosis due to early diagnosis challenges and treatment resistance. Thymidylate synthetase (TYMS), a key enzyme in DNA synthesis, has been associated with poor prognosis in multiple cancers, yet its multi‐omics characteristics in LUAD remain systematically uncharacterized. This study focuses specifically on LUAD, integrating transcriptomic, proteomic, and genomic data to elucidate TYMS expression patterns, prognostic value, immune microenvironment interactions, and therapeutic potential. Using data from The Cancer Genome Atlas (TCGA), the Clinical Proteomic Tumour Analysis Consortium (CPTAC), the Genome‐Tissue Expression Project (GTEx), the Gene Expression Profile Interaction Analysis (GEPIA2), etc., we conducted comprehensive bioinformatics analyses of TYMS in LUAD. TYMS showed significant overexpression at both mRNA and protein levels in LUAD tissue. High TYMS expression correlated with earlier tumour staging, higher histological grade, and poor prognosis. Functional enrichment analysis revealed TYMS involvement in p53/Rb and mammalian Target of Rapamycin (mTOR) signalling pathways. TYMS expression was associated with immune cell infiltration, showing negative correlation with B‐cell activity and positive correlation with neutrophil infiltration, as well as significant association with Cytotoxic T Lymphocyte‐Associated Protein 4 (CTLA4), Programmed Death‐1 (PDCD1, PD‐1), and Interleukin‐6 (IL‐6). Somatic copy number variation (SCNA) analysis indicated that TYMS amplification was linked to poor prognosis and enriched in the folate metabolism pathways. Drug sensitivity analysis demonstrated that high TYMS expression positively correlated with sensitivity to Afatinib and Gefitinib, but negatively correlated with Methotrexate and Vorinostat. In conclusion, TYMS is upregulated in LUAD and may serve as an independent prognostic biomarker and therapeutic target.