Fig. 1

Cellular regulation mechanisms of radioresistance. (A) Normal stem cells are transformed into cancer stem cells through gene mutation or abnormal expression, and different ESCC cell subsets are separated according to the specific markers on them. (B) In the cell cycle, the G1 checkpoint is responsible for the cell size, nutrients, growth factors and DNA damage; the G2 checkpoint is responsible for the cell size and DNA replication; the M checkpoint is responsible for the chromosome attachment to spindle. DNA-PK regulates the response of G1/S checkpoint to DNA double strand breaks (DSB); ATR activates downstream Chk1 or ATM activates downstream Chk2, p53 and other protein, which starts the arrest in S-phase cell cycle; ATM and ATR induced G2/M phase arrest. (C) Mitochondrial hypoxia leads to the increase of ROS release, which promotes the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) to combine with the antioxidant response element (ARE) in the promoter region of the target gene, and activates related antioxidant molecules, such as NADPH, heme oxygenase-1(HO1), and NADPH:quinone oxidoreductase-1(NQO1) driven by Nrf2. So as to reduce or eliminate the generation of ROS, prevent cancer cell damage caused by redox, and enhance the radioresistance of tumors. (D) Hypoxia or tumor-related fibroblasts promote the expression of EMT markers such as slug, snail and Zeb1 by inducing TGF-β activation and paracrine, and mediate the radioresistance mechanism of ESCC. (E) Autophagy-mediated tumor survival is mainly attributed to: (i) clearing dysfunction through mitochondrial autophagy and regulating oxidative stress to promote EMT’s response to GSK-β. (ii) Genomic instability caused subsequently. AMP-activated protein kinase (AMPK) activates autophagy, while mammalian target of rapamycin complex 1 (mTORC1) does the opposite