Epigenetic reprogramming of lineage switching in cancer

Lineage plasticity develops as tumor cells overcome terminal differentiation barriers, adapt to environmental stressors, and acquire metastatic, therapy‐resistant phenotypes. These phenotypic transitions are driven by nonmutational epigenetic mechanisms, including dynamic shifts in chromatin accessibility, histone modifications, DNA methylation, and noncoding RNA activity beyond genetic alterations. While epithelial–mesenchymal plasticity (EMP) remains a foundational model, cancer‐cell plasticity extends into a broader pan‐plasticity spectrum encompassing dedifferentiation, transdifferentiation into neuroendocrine or squamous lineages, and stem cell–like reprogramming. In this review, we evaluate how the antagonistic interplay between Polycomb and Trithorax complexes, chromatin modifier activity, and enhancer reprogramming affects lineage identity and enables multi‐lineage plasticity in cancer. We further discuss extrinsic mechanisms reinforced by the tumor microenvironment, particularly hypoxia, chronic inflammation, and metabolic stress, that rewire the epigenetic landscape to stabilize plastic states. Collectively, these data underscore epigenetic deregulation as a primary driver of lineage plasticity and intratumoral heterogeneity, while revealing therapeutic vulnerabilities and the potential to reverse plasticity and overcome therapy resistance by targeting the epigenome.