Lactylation-related gene signatures for prognosis and treatment response prediction in radiation-resistant non-small cell lung cancer.

BACKGROUND: Lactylation, as a novel type of post-translational protein modification, is closely associated with key processes such as cellular metabolism, the tumor immune microenvironment, tumor proliferation, and metastasis. However, the specific relationship between lactylation and radiation resistance in non-small cell lung cancer (NSCLC) has not yet been fully explored. This study aims to investigate the potential relationship between lactylation and radiation resistance in lung cancer using tumor databases, providing new molecular targets for individualized radiotherapy strategies for NSCLC. METHODS: Using the Cancer Genome Atlas (TCGA) database and the GSE197236 dataset on non-small cell lung cancer, the differential expression of lactate-associated radiation resistance genes (LARRGs) was analyzed. Based on the lactylation-radiation resistance model, relevant risk scores were calculated to identify high-lactylation and low-lactylation subtypes. A gene signature model based on LARRGs was developed and validated, and it was evaluated using training and validation cohorts. Additionally, immune cell infiltration and drug response were analyzed. RESULTS: A total of 1865 differentially expressed genes (DEGs) were identified, showing differences between radiation resistant non-small cell lung cancer (NSCLC) and normal tissues. Among these genes, 23 lactate-related differentially expressed genes (LR-DEGs) were ultimately identified through an intersection analysis of the DEGs and LARRGs. Using univariate and multivariate Cox regression analysis for further screening, three key lactate-related biomarkers were identified: RRM2B, COL4A1, and CD46. It was found that patients with high-LARRGs exhibited stronger characteristics of immune exclusion, immune exhaustion, and immunosuppression in the tumor microenvironment (TME). Additionally, in the scRNA-seq, different cell types are distinctly distributed in the reduced-dimensional space, reflecting the significant heterogeneity of the TME. Furthermore, the gene sets of fibroblasts and endothelial cells show the highest scores, suggesting that under high lactate conditions, enhanced gene expression activity in fibroblasts and endothelial cells may promote tumor radioresistance. Analysis of significantly correlated signaling pathways in the high-LARRGs indicates that metabolic reprogramming and immunosuppression may promote radioresistance through lactate-mediated inhibition of T cell function and macrophage polarization, which highlights the role of the TME in radiotherapy and suggests that targeting immune evasion mechanisms may be a key strategy to overcome radioresistance. CONCLUSIONS: LARRGs are crucial in the context of radiation resistant NSCLC, as they significantly influence tumor growth, the immune microenvironment, and drug response. This signature of LARRGs has the potential to serve as a prognostic biomarker and may also represent a promising therapeutic target for patients facing radiation resistant NSCLC.