Extrachromosomal DNA as a platform for epigenetic reprogramming in cancer.

Extrachromosomal DNA (ecDNA) has emerged as a major contributor to cancer aggressiveness, yet its role extends far beyond its classical definition as a vehicle for oncogene amplification. Recent studies indicate that ecDNA functions as a dynamic regulatory platform that reshapes chromatin accessibility, enhancer activity, three-dimensional genome organization, nuclear architecture, and transcriptional output. Through these properties, ecDNA enables cancer cells to amplify oncogenic signaling, generate transcriptional plasticity, and rapidly adapt to selective pressures. In contrast to chromosomal amplification, ecDNA is structurally independent, frequently circular, acentromeric, and inherited through noncanonical mitotic behaviors, allowing unequal segregation, coordinated co-inheritance, and persistent propagation of advantageous regulatory states. Emerging evidence further shows that ecDNA can hijack pre-existing enhancers, rewire enhancer-oncogene communication, activate noncanonical regulatory elements, and assemble into transcriptionally active nuclear hubs and condensate-associated structures, thereby transforming genome rearrangement into epigenetic innovation. These mechanisms position ecDNA as a key driver of intratumoral heterogeneity, clonal evolution, metastatic adaptation, and therapeutic resistance. At the same time, the high transcriptional burden and specialized regulatory architecture of ecDNA-positive tumors may create selective vulnerabilities, including transcription-replication conflict and dependence on ecDNA-associated hubs, condensates, and regulatory modules. In this review, we synthesize current advances in the formation, regulation, inheritance, and functional consequences of ecDNA, with a particular focus on its emerging role as a platform for epigenetic reprogramming in cancer. We also discuss how this conceptual shift from copy-number biology to regulatory biology may redefine ecDNA as both a mechanistic framework for tumor plasticity and a potential frontier for precision oncology.