Nuclear Mechanotransduction in Cancer Radiation Response: Linking Nuclear Envelope Dynamics to DNA Damage Repair

Tumor mechanics influence radiation response, yet no single mechanical parameter predicts radiosensitivity, and nominally identical variables report opposite results. The gap is not a shortage of mechanisms but the absence of a validated link between a measurable nuclear state, the fidelity of damage processing, and long-term reproductive outcome. This review follows mechanical signals from adhesion and the cytoskeletal systems through the linker of nucleoskeleton and cytoskeleton (LINC) complex, nuclear pores and lamina to chromatin, the nucleolus and DNA repair, asking at each step whether the mechanical input could change how radiation damage is processed rather than how much is produced. Mechanical manipulation combined with irradiation in the same system remains uncommon; most evidence establishes mechanosensitive components without connecting them to a radiation outcome, and this asymmetry accounts for much of the apparent conflict in the literature. We therefore sort the evidence into three levels of support, propose a three-state framework of nuclear mechanical homeostasis (insufficient structural support, maladaptive structural constraint, coordinated integrity and plasticity), and specify the experiments that would falsify it. Nuclear mechanotransduction is better described as a context-dependent adaptive network than as a single determinant of radiosensitivity, and matrix-normalizing, Src-directed and ultrasound-based interventions remain unvalidated for radiotherapy.