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Figure 1. Mechanisms related to CSCs radioresistance in HNSCC. Radiation can activate stemness pathways such as Sox-2 and Oct3/4 and induce CSC phenotype in non-stem cancer cells. Radiation promotes an arrest of CSCs in the G2/M phase and activates Chk2 and Chk1, which delays cell cycle progression and allows DNA repair. Overexpression of CSC marker ALDH1 leads to increased rates of sub-lethal damage repair (SLDR), enabling efficient cell repair and reducing tumor control capabilities. CSCs upregulate anti-apoptotic proteins such as Bcl-2 and X-linked inhibitors of apoptosis (XIAP). Hypoxia upregulates CSCs genes (Sox2 and Nanog) and is essential in protecting the CSCs niche from radiation effects. GDF15 (growth differentiation factor 15) participates in ROS suppression in HNSCC, contributing to radioresistance and acquisition of the CSC phenotype.