Nuclear Pore Mechanotransduction in Oncology: A Structural Axis of Vulnerability for Targeted Intervention

Abstract

ABSTRACT Nuclear pore complexes (NPCs) are massive protein assemblies that gate the nuclear envelope to regulate nucleocytoplasmic transport. Beyond their canonical role as conduits, NPCs act as mechanosensitive regulators that translate cytoskeletal, extracellular, and lamina‐derived forces into transport decisions coupled to cellular state. In malignancy, NPCs undergo extensive remodeling—marked by protein overexpression, hyperpermeability, and compromised scaffold integrity. While these alterations drive invasion and transcriptional plasticity, they simultaneously expose a lethal mechanical vulnerability; transformed cells become critically dependent on this altered NPC state. We propose the “nuclear mechanostat” as a testable conceptual framework in which NPC barrier stringency and nuclear mechanics are reciprocally coupled. Through the lenses of dilation, elastic deformation, and structural memory, we synthesize existing evidence and develop the hypothesis that pharmacological disruption of the permeability barrier or scaffold architecture erodes nuclear resilience. Because cancer cells operate near a mechanical failure threshold, targeting these conserved mechanotransducers reveals a pan‐cancer axis of vulnerability, opening new frontiers for precision oncology.