Beyond DNA Damage: 3D Tumor Models and the Integrin Mechanobiology of Radioresistance

Despite major advances in radiation delivery, clinical outcomes remain constrained by tumor biology rather than technology. Conventional radiobiology has relied on reductionist two-dimensional (2D) systems that fail to capture the spatial, mechanical, and multicellular organization of tumors. Three-dimensional (3D) tumor models now resolve radiation response as a mechanobiological process coordinated across the extracellular matrix (ECM), adhesion signaling, cytoskeleton, and nucleus. This review focuses on a specific and we argue, underappreciated intersection: how 3D models expose integrin-mediated mechanotransduction as a determinant of the DNA damage response (DDR) and therapy resistance epitomized by cell adhesion-mediated radioresistance (CAM-RR) - an organizing principle we frame as the ECM-integrin-nucleus axis. We first delineate which model classes resolve which layer of this biology, distinguishing effects of three-dimensional organization from those of defined ECM-integrin signaling, and we treat the underlying mechanobiology quantitatively rather than descriptively. We then develop a mechanistic framework linking ECM architecture and stiffness to integrin-RTK crosstalk, cytoskeletal tension, LINC-mediated force transfer, and chromatin-dependent DNA repair, in which radiosensitivity emerges as a property of tissue context. From a translational standpoint, 3D models enable functional, radiation-specific assessment of context-dependent radiosensitivity and of mechanically targeted radiosensitization, while their integration with quantitative imaging and computational approaches further supports biomarker-guided and adaptive treatment strategies. We close with testable predictions that this framework generates, intended to guide the next phase of biology-driven radiation oncology.