From ecDNA structure to tumor immune escape and therapeutic resistance: evidence, uncertainty, and clinical priorities
Year: 2026
Type: review
Abstract: Extrachromosomal DNA (ecDNA) is a structurally distinct form of focal amplification that can increase oncogene dosage, reorganize enhancer-promoter interactions, and accelerate tumor evolution through unequal segregation. This review presents a single, evidence-based sequence: the structure of ecDNA confers an evolutionary capacity; selection then acts upon the genes and regulatory elements that are carried by ecDNA; the clones that have been selected may subsequently develop treatment-adaptive or immune-associated traits; and clinical application can only proceed once it has been demonstrated that ecDNA provides information that goes beyond what is seen in conventional amplification. The strongest evidence comes from unequal segregation, regulatory rewiring in specific models, reversible copy-number adaptation during targeted therapies, and replication-stress vulnerabilities in preclinical systems. In contrast, associations with reduced antigen presentation, altered interferon signaling, immune-cell exclusion, chemotherapy resistance, radiotherapy response, and immunotherapy failure remain context-dependent and not universally causal. When discussing the cGAS-STING pathway, intact nuclear ecDNA is differentiated from micronuclear DNA and damaged cytosolic fragments. Therapeutic strategies are classified based on direct preclinical evidence for ecDNA specificity, ecDNA-associated evidence, indirect biological reasoning, or a conceptual hypothesis; no strategy is presented as an established treatment directed at ecDNA. Detection methods are arranged from amplification screening to breakpoint-resolved inference to independent physical confirmation. Clinically useful driver biomarkers are separated from candidate ecDNA biomarkers that require prospective validation. The main conclusion is that ecDNA is an established driver of tumor evolution but has not yet been broadly validated as an immune-evasion mechanism, a predictive biomarker, or a routine therapeutic target.
Source: Frontiers in Oncology
Author: Shafee Ur Rehman
Institutions: University of South Asia, University of South Asia
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7223298017