3D chromatin architecture in cancer: mechanisms of dysregulation and emerging therapeutic strategies

The three-dimensional (3D) genome architecture is fundamental to orchestrating gene expression, safeguarding genome integrity and establishing cell-type-specific transcriptional landscapes. In cancer, this spatial genome architecture becomes profoundly disrupted through alterations in DNA regulatory elements, dysregulation of architectural proteins such as CCCTC-binding factor and cohesin, aberrant chromatin looping, and the breakdown or rewiring of topologically associating domains. Such structural perturbations can activate oncogenic enhancers and super-enhancers, promote inappropriate promoter–enhancer communication, and facilitate large-scale chromatin reprogramming that drives malignant cell states. Recent advances in high-resolution genome conformation technologies including Hi-C, HiChIP and single-cell 3D genomics have uncovered widespread spatial reorganization across diverse tumour types, revealing mechanisms of cancer progression that extend far beyond linear mutations. This review synthesizes current insights into how 3D chromatin structure is altered in cancer, elucidates molecular pathways linking structural dysregulation to oncogenesis and evaluates emerging therapeutic strategies targeting 3D genome architecture, from epigenetic modulators to enhancer disruption and phase-separation-based interventions.