Role of Mitochondria‐Related Genes in NSCLC: Prognostic Implications and Immune Microenvironment Influence

Background: The role of mitochondria‐related genes on non‐small‐cell lung cancer (NSCLC), which encompasses lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), remains inadequately understood. This study investigates their influence on prognosis, immune microenvironment, and response to immunotherapy. Methods: We analyzed NSCLC data from The Cancer Genome Atlas to assess gene expression differences, Kaplan–Meier survival curves, and Cox regression. A prognostic model was developed using machine learning techniques. Functional enrichment and pathway analyses were performed using Gene Ontology, the Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis. Single‐cell RNA sequencing data from the TISCH2 database were examined to elucidate key gene expressions. Tumor Mutation Burden and differential mutation frequencies were evaluated. The ESTIMATE and TIDE algorithms were utilized to analyze the immune microenvironment and predict responses to immunotherapy. Results: Significant mitochondria‐related genes were identified in both LUAD and LUSC. The StepCox [both] + Ridge model, which included 13 genes, exhibited the highest prognostic accuracy. Functional analyses indicated that these genes are involved in KRAS signaling, angiogenesis, and glycolysis. Single‐cell analysis revealed that KLK6 expression is primarily localized in malignant and epithelial cells. Mutation analysis indicated that PTEN and ASPM mutations were more prevalent in low‐risk groups, whereas CACNA1C and CSMD1 mutations were more common in high‐risk groups. Nine genes showed strong correlations with immune scores. TIDE analysis suggested that high‐risk patients may have a better response to immunotherapy, a finding corroborated by submap analysis in high‐risk LUSC patients. Conclusion: Mitochondria‐related genes significantly impact the prognosis of NSCLC and may influence the immune microenvironment and responses to immunotherapy. These findings enhance our understanding of NSCLC and suggest potential targets for future therapeutic interventions.