Nanomechanical Single-Cell Profiling Reveals Mechanical Dormancy Underlying Radiation Resistance in Polyploid Giant Cancer Cells.

Radiation therapy induces DNA damage primarily through reactive oxygen species, leading to cancer cell apoptosis. However, intratumoral heterogeneity and spatial dose variations often result in the survival of polyploid giant cancer cells (PGCCs), a therapy-resistant subpopulation characterized by multinucleation, genetic instability, and stem-like features. Particularly in malignant breast cancer, PGCCs contribute to recurrence by adopting a dormant yet invasive phenotype. Despite their clinical relevance, reliable tools to identify or characterize these cells remain lacking. Here, we present a nanomechanical single-cell profiling platform that enables high-resolution mechanomics of radiation-induced PGCCs. Through integrated cytoskeletal imaging and nanoscale stiffness mapping, we identify a distinct mechanical dormancy state, marked by cortical actin remodeling, nuclear enlargement, and biomechanical stiffening. This dormant mechanotype is coupled with suppressed proliferation yet sustained expression of invasion-associated markers, representing a latent therapeutic threat. Our findings position mechanical dormancy as a mechanobiological hallmark of radiation resistance and propose a predictive framework for optimizing radiotherapy thresholds. This platform enables mechanotype-guided stratification and precision-targeted intervention in radiation-refractory cancer.