Telomerase-related gene EHHADH drives lung cancer progression and shapes the immunosuppressive tumor microenvironment

Background Lung cancer is a leading cause of cancer-related mortality, necessitating accurate prognostic assessment and optimized treatment. Telomerase-related genes are pivotal in tumor development, yet their prognostic value and mechanisms within the lung cancer tumor microenvironment (TME) remain unclear. Methods We analyzed telomerase-related gene mutations in lung cancer (TCGA) and identified eight key prognostic genes (INMT, ALDH3A2, OGDHL, TDO2, EFNA3, STAT1, EHHADH, AANAT) from seven public datasets via Cox regression. A robust prognostic risk model was built and validated across independent cohorts. TME associations were explored using IPS, ESTIMATE scores, and immune infiltration analyses. EHHADH's functional role was validated via immunohistochemistry, in vitro knockdown, and single-cell RNA sequencing. Results Our model demonstrated strong predictive performance and consistently outperformed existing prognostic signatures across multiple datasets. Importantly, low-risk patients exhibited an “immune-hot” phenotype with higher IPS scores and enhanced immune cell infiltration, suggesting potential sensitivity to immunotherapy. In contrast, high-risk patients displayed an immunosuppressive microenvironment. Among the model genes, EHHADH emerged as a key oncogenic driver, positively associated with risk score and poor survival. Functional assays revealed that EHHADH promotes tumor cell migration while reducing adhesion. Single-cell analysis further demonstrated that EHHADH is predominantly expressed in epithelial cells and is associated with an “immune-desert” TME characterized by reduced immune infiltration. Conclusion This study establishes a clinically relevant telomerase-related gene signature that enables effective risk stratification and provides insights into tumor-immune interactions in lung cancer. Notably, EHHADH is identified as a potential therapeutic target that contributes to immune evasion and tumor progression. These findings offer a foundation for personalized prognostic assessment and suggest that targeting EHHADH may enhance the efficacy of immunotherapy in lung cancer patients.