Abstract
Lung cancer remains a leading cause of cancer-related mortality worldwide, and immunotherapy has emerged as a promising treatment modality. However, its efficacy is limited to a subset of patients, necessitating predictive biomarkers for personalized treatment strategies. DNA methylation (DNAm) is increasingly recognized as a crucial regulators of gene expression and immune responses in the tumor microenvironment. This review focuses on DNAm as a key epigenetic biomarker for predicting and enhancing immunotherapy efficacy in lung cancer. We highlight DNAm changes in key immune-related genes and their association with tumor phenotype, immune cell infiltration, and response to immune checkpoint inhibitors (ICIs). The review also evaluates established and emerging genomic and non-genomic biomarkers, including tumor mutational burden (TMB), microsatellite instability (MSI), PD-L1 expression, tumor-infiltrating lymphocytes (TILs), and immunosuppressive cytokines in case of lung cancer immunotherapy. Furthermore, the potential for integrated epigenetic signatures and minimally invasive diagnostic approaches, such as liquid biopsies, is discussed. Finally, we address the challenges and future directions for translating epigenetic biomarkers into clinical practice to improve immunotherapy outcomes and reduce immune-related adverse events.