Fotinos, J.; Condat, C. A.; Barberis, L.

Cancer stem cells (CSCs) exhibit increased resistance to radiotherapy, contributing to tumor recurrence and progression. While CSCs are known for their intrinsic resistance, the role of their spatial organization remains poorly understood. We extend a computational model of tumorsphere growth to investigate how the spatial distribution of CSCs influences radiation response. The model explicitly tracks cell lineages and spatial positions, revealing a preferential accumulation of CSCs in the spheroid interior. Because radiosensitivity increases with oxygen availability, and oxygen levels are lowest in the tumor core, this spatial organization confers a protective advantage to the CSC population. We find that this effect is negligible in small, well-oxygenated tumorspheres but becomes pronounced as growth leads to the emergence of hypoxic regions. To isolate the role of spatial structure, we compare these results with control simulations in which CSC positions are randomly reassigned. In these synthetic configurations, CSC survival under irradiation is markedly reduced, demonstrating that spatial localization is a key determinant of radioresistance. This effect persists even after the onset of central necrosis, suggesting that the "spatial niche" of CSCs is a critical target for improving therapeutic outcomes.