Immunometabolic Features and Key Biomarkers in Lung Cancer Complicated by Pulmonary Tuberculosis: Insights From Transcriptome and Clinical Cohort Analysis

ABSTRACT Coexisting lung cancer and pulmonary tuberculosis (LC‐PTB) is clinically challenging in diagnosis and treatment, and its mechanisms are unclear. This study aimed to explore its immune and molecular basis to identify diagnostic biomarkers. We prospectively enrolled LC patients, LC‐PTB patients, and controls. Lymphocyte subsets were analyzed by flow cytometry. Key markers were identified through blood transcriptome sequencing and bioinformatics (differential expression, GSEA, GO/KEGG), and validated by RT‐qPCR and immunohistochemistry. Analysis included 138 subjects (50 controls, 50 LC, 38 LC‐PTB). Compared to LC alone, LC‐PTB demonstrated significantly increased CD4 + T cells ( p = 0.0064) and NK cells ( p = 0.0447), with an elevated CD4/CD8 ratio. Transcriptome analysis identified 144 upregulated and 435 downregulated genes in LC‐PTB versus controls, and 216 upregulated and 388 downregulated genes versus LC alone (|Fold Change| ≥ 2, p < 0.05). Enrichment analysis revealed involvement of antigen presentation, oxidative phosphorylation, and nitrogen metabolism. Six key genes (ANK2, EPB42, CA1, HBB, HBD, MYL4) were identified. A four‐gene model (CA1, HBD, MYL4, ANK2) discriminated LC‐PTB from LC (AUC 0.940, 95% CI 0.846–1.000). We provide the first immune‐transcriptomic map of LC‐PTB and a validated four‐gene diagnostic signature ready for external evaluation.