Epigenetics in lung cancer precision medicine: from bench to bedside—a narrative review

Background and Objective: Lung cancer ranks among the most prevalent malignancies globally. Despite progress in early detection and standard therapies lowering overall mortality, there remains an urgent demand for optimized combinatorial regimens, reliable biomarkers and individualized strategies to advance precision lung cancer care. Epigenetic-targeted agents, represented by DNA methylation and histone lysine deacetylase (HDAC) inhibitors, have exhibited encouraging anti-tumor effects, and the Food and Drug Administration (FDA)-approved EZH2 inhibitor tazemetostat has further validated the translational value of epigenetic therapy across multiple tumors. This narrative review systematically summarizes epigenetic alterations and corresponding targeted inhibitors in lung cancer, and clarifies the clinical prospects of epigenetic tools for diagnostic biomarker development and stratified precision treatment.

Methods: We searched PubMed and Web of Science Core Collection from database inception to January 31, 2026 with keywords covering lung cancer, DNA methylation, histone modification and epigenetic targeted therapy. Only full-text English original articles and reviews were retained.

Key Content and Findings: This review systematically characterizes aberrant epigenetic signatures in lung cancer, encompassing DNA methylation, histone methylation, and the recently discovered histone lactylation, while detailing epigenetic biomarkers applicable to diagnosis and targeted therapy. We further summarize subtype-specific research advances of KMT/KDM, HDAC, EZH2 and LSD1 inhibitors in distinct lung cancer subtypes, with core functions including suppressing tumor proliferation, modulating neuroendocrine phenotypic transition, reversing therapeutic resistance, and amplifying anti-tumor immune responses.

Conclusions: Dysregulated epigenetic modifications serve as core drivers of lung cancer progression, and various epigenetic small-molecule inhibitors possess broad application potential for lung cancer precision treatment. Combined regimens integrating epigenetic agents with immunotherapy or chemotherapy can strengthen anti-tumor responses, yet subtype heterogeneity and unsatisfactory clinical efficacy of some targeted drugs remain major obstacles. The accumulated preclinical and clinical epigenetic evidence summarized herein provides solid theoretical support for developing novel diagnostic biomarkers and individualized stratified therapeutic strategies against lung cancer.