Methylation Analyses in Liquid Biopsy of Lung Cancer Patients: A Novel and Intriguing Approach Against Resistance to Target Therapies and Immunotherapies

Background/Objectives: As one of the intensely studied epigenetic modifications, DNA methylation plays a key role in tumours, including lung cancer. Hypermethylation in tumour suppressor genes or hypomethylation in oncogenes is an important event in tumorigenesis. Minimally invasive detection of aberrant DNA methylation by liquid biopsy could provide invaluable biomarkers for lung cancer screening, early diagnosis, prognosis, and treatment, also providing a useful tool to monitor response to targeted therapies and immunotherapies. Methods: Here, we discuss the current state-of-the-art cfDNA methylation analysis of NSCLC patients, examine the unique features and limitations of detection methods in a clinical context, and highlight the last research findings in the context of main biological and immunological therapies in lung cancer. Thus, the main goal of this review is to provide a critical overview of the most important published studies that report cfDNA methylation as prognostic biomarker for resistance to target therapies and immunotherapies in lung cancer. Results and Conclusions: DNA methylation-based biomarkers show promise for lung cancer detection and management. In particular, ctDNA methylation has been shown to play an important role in detecting resistance to tyrosine kinase inhibitors and immunotherapies. Nonetheless, DNA methylation biomarkers still lack large-scale validation, actually precluding their rapid implementation in clinical practice.