The study investigates the impact of cell migration on nuclear envelope (NE) integrity and DNA damage in cancer cells. During migration through tight interstitial spaces, tumor cells experience significant deformation, leading to localized loss of NE integrity. This results in the uncontrolled exchange of nucleo-cytoplasmic content, chromatin herniation across the NE, and DNA damage. The incidence of NE rupture increases with cell confinement and depletion of nuclear lamins, which are essential for NE structural support. Cells repair NE integrity using components of the endosomal sorting complexes required for transport-III (ESCRT-III) machinery. The findings suggest that efficient NE and DNA damage repair are crucial for cell survival during migration. The study also proposes a biophysical model where cytoskeletal-generated nuclear pressure causes the formation and eventual rupture of nuclear membrane blebs at sites of high membrane curvature and weak nuclear lamina. This process is particularly prominent in cells with reduced lamin levels, which are common in many cancers. The results highlight the potential of targeting NE repair and DNA damage repair pathways as a strategy to develop anti-metastatic drugs.The study investigates the impact of cell migration on nuclear envelope (NE) integrity and DNA damage in cancer cells. During migration through tight interstitial spaces, tumor cells experience significant deformation, leading to localized loss of NE integrity. This results in the uncontrolled exchange of nucleo-cytoplasmic content, chromatin herniation across the NE, and DNA damage. The incidence of NE rupture increases with cell confinement and depletion of nuclear lamins, which are essential for NE structural support. Cells repair NE integrity using components of the endosomal sorting complexes required for transport-III (ESCRT-III) machinery. The findings suggest that efficient NE and DNA damage repair are crucial for cell survival during migration. The study also proposes a biophysical model where cytoskeletal-generated nuclear pressure causes the formation and eventual rupture of nuclear membrane blebs at sites of high membrane curvature and weak nuclear lamina. This process is particularly prominent in cells with reduced lamin levels, which are common in many cancers. The results highlight the potential of targeting NE repair and DNA damage repair pathways as a strategy to develop anti-metastatic drugs.