Unlocking Lung Cancer Cell Dormancy: An Epigenetic Perspective

Lung cancer remains one of the leading causes of cancer-related mortality worldwide, with tumor recurrence and metastasis posing significant challenges despite advances in targeted therapies and immunotherapy. Cellular dormancy, a reversible, quiescent state marked by cell cycle arrest, has emerged as a key driver of therapeutic resistance and disease relapse, particularly in small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Multiple mechanisms, including autophagy, stress-adaptive signaling, microenvironmental cues, and epigenetic dysregulation, have been implicated in the regulation of dormancy and long-term cell survival. Among these, epigenetic modifications such as DNA methylation, histone modifications, and non-coding RNAs (ncRNAs) play pivotal roles in maintaining dormancy by repressing proliferative gene expression programs. Increasing evidence suggests that dormant tumor cells harbor distinct epigenomic signatures, which may serve as predictive biomarkers for minimal residual disease (MRD) and relapse risk. This review summarizes current advances in understanding the epigenetic regulation of cellular dormancy in lung cancer, with a particular emphasis on the interplay between epigenetic modifiers and oncogenic signaling pathways. Furthermore, emerging molecular targets and associated therapeutic agents currently under clinical evaluation are presented, emphasizing how a deeper understanding of the epigenetic landscape governing dormancy may inform the development of novel interventions to improve long-term clinical outcomes in lung cancer patients.