DNA Methylation in Lung Cancer: Predictive Biomarkers for Effective Immunotherapy

Komal Kumari,1 Vinay Kumar,2 Chaitenya Verma,3 Ping-Ching Hsu,4 Amarnath Singh4 1Department of Biotechnology, Central University of South Bihar, Gaya, BR, 824236, India; 2Heart and Vascular Institute, Pennsylvania State University, Hershey Medical Center, Hershey, PA, 17033, USA; 3Department of Biotechnology, Sharda University, Greater Noida, UP, 201310, India; 4Department of Environmental Health Sciences, Fay W.Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USACorrespondence: Amarnath Singh, Department of Environmental Health Sciences, Fay W.Boozman College of Public Health, University of Arkansas for Medical Sciences, UAMS Winthrop P. Rockefeller Cancer Institute, 11th Floor, CI.11172/11208, Little Rock, AR, 72205, USA, Email [email protected] Ping-Ching Hsu, Department of Environmental Health Sciences, Fay W.Boozman College of Public Health, University of Arkansas for Medical Sciences, 4301 W Markham St., #820, Rm 1224, Little Rock, AR, 72205, USA, Email [email protected]: 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. Keywords: tumor mutational burden, tumor microenvironment, epigenetic biomarkers, immunotherapy, microsatellite instability, tumor-infiltrating lymphocytes