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REVIEW

Extrachromosomal DNA in Solid Tumors—Landscape, Immune Effects, and Resistance to Targeted Therapy

Omar Badran1,2,*, Siraj Attarya3
1 Department of Oncology, Emek Medical Center, Afula, Israel
2 Technion Integrated Cancer Center, Faculty of Medicine, Technion, Haifa, Israel
3 The Arab National Society for Health Research and Services, The Galilee Society, Shafa Amr, Israel
* Corresponding Author: Omar Badran. Email: email
(This article belongs to the Special Issue: Identification of potential targets and biomarkers for cancers and the exploration of novel molecular mechanisms of tumorigenesis and metastasis)

Oncology Research https://doi.org/10.32604/or.2026.075916

Received 11 November 2025; Accepted 21 February 2026; Published online 11 March 2026

Abstract

Extrachromosomal DNA (ecDNA) constitutes a principal factor in the amplification of oncogenes and the progression of tumors in solid malignancies. This review synthesizes emerging mechanistic, genomic, and immunologic evidence across multiple tumor types, including glioblastoma, lung, breast, gastrointestinal, hepatobiliary, urothelial, prostate, gynecologic, pediatric, and head-and-neck cancers, with the goal of clarifying the role of ecDNA in immune escape and therapy resistance and outlining its translational implications for precision oncology. ecDNA comprises substantial acentromeric circular elements that serve as transcriptional hubs, modulate enhancer–promoter interactions, and undergo dynamic copy-number cycling, thereby fostering intratumoral heterogeneity and resistance to therapy. Recurrent oncogenic cargos, including epidermal growth factor receptor (EGFR), v-myc avian myelocytomatosis viral oncogene homolog (MYC), erb-b2 receptor tyrosine kinase 2, also known as human epidermal growth factor receptor 2 (ERBB2/HER2), and cyclin D1 (CCND1), are frequently located in ecDNA. They can interconvert with intrachromosomal homogeneously staining regions (HSRs) under treatment pressure. Emerging evidence links ecDNA to an immune-cold phenotype, characterized by downregulation of antigen presentation and decreased responsiveness to immune checkpoint inhibitors. We further emphasize diagnostic and translational methodologies that incorporate ecDNA detection through liquid biopsy and the spatial mapping of tumor topology. Finally, we propose a comprehensive clinical implementation framework that integrates ecDNA profiling, longitudinal monitoring, and immune microenvironment assessment to guide precision therapy. Gaining a deeper understanding of ecDNA biology has the potential to ultimately transform it from merely a prognostic biomarker into a targetable element within cancer therapy.

Keywords

Extrachromosomal DNA (ecDNA); double minutes; enhancer hijacking; immune-cold tumors; targeted-therapy resistance; liquid biopsy

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