Targeting extrachromosomal DNA in human cancers

Extrachromosomal DNAs (ecDNAs) are acentric circular DNA elements that frequently mediate oncogene amplification and genomic rearrangements in human cancers. Found across diverse adult and paediatric malignancies, ecDNA drives rapid tumour evolution, metabolic adaptation and treatment resistance. Its presence in precancerous lesions and association with poor outcome underscore the need for improved detection and therapeutic targeting. Recent advances have substantially expanded our understanding of ecDNA biology, revealing mechanisms underlying oncogene plasticity and treatment failure. This Review synthesizes key findings on ecDNA biology, the challenges faced by current therapeutic and detection approaches and the recent discoveries that point to emerging therapeutic vulnerabilities. We propose future directions to ecDNA-focused therapeutic development, including the utility of chemical proteomics approaches, and discuss efforts required to integrate ecDNA diagnostics into the clinic, presenting a roadmap from bench to bedside.