• DNA-PKcs localizes to centromeres during mitosis and is phosphorylated in the nucleus during interphase, linking it to primary cilia dynamics.
• Ionizing radiation induces persistent primary cilia formation in senescent tumor cells, which is dependent on DNA-PKcs activity.
• Disruption of primary cilia or DNA-PKcs enhances tumor cell radiosensitivity and promotes senescent cell death.
• The DNA-PKcs-primary cilia axis represents a potential therapeutic target to overcome radioresistance in cancer treatment.