Fig. 1

The mechanisms of RT-induced apoptosis and necroptosis in tumor cells. RT induces tumor cell apoptosis through the intrinsic pathway and the extrinsic pathway. In the intrinsic pathway, ionizing radiation damages DNA, leading to the activation of ATM and p53, which subsequently act on downstream molecules. These molecules alter the permeability of the mitochondrial membrane, leading to the release of cyt-c. Cyt-c interacts with Apaf-1 and pro-caspase-9 to activate caspase-9. Caspase-9 promotes the maturation of caspase-3 and leads to apoptosis. In the extrinsic pathway, TNF-αbinds to its receptor and subsequently recruits TRADD, cIAP1, cIAP2, TRAF2, and RIPK1 to form complex I. Complex I forms various complexes through deubiquitination. Complex IIa is composed of TRADD, FADD, and caspase-8, which can lead to the activation of caspase-8 and activate caspase-3 to promote apoptosis. Necroptosis is associated with the activity of caspase-8. When caspase-8 is activated, it can form complex IIb with RIPK1, RIPK3, and FADD, inactivate RIPK1 and RIPK3, and eventually lead to apoptosis; when caspase-8 is inactivated, complex IIc is formed. RIPK1 activates RIPK3, which recruits and activates MLKL. MLKL oligomerizes and changes the permeability of cell membranes, promoting necroptosis. Apaf-1: apoptotic protease activating factor-1; CAD: caspase-activated deoxyribonuclease; cIAP: cellular inhibitor of apoptosis protein; cyt-c: cytochrome-c; FADD: Fas-associating protein with a novel death domain; IKK: inhibitor of NF-κB (IκB) kinase; MLKL: mixed lineage kinase domain-like protein; RIPK: receptor-interacting serine/ threonine-protein kinase; RT: radiotherapy; TRADD: TNF receptor-associated death domain; TRAF2: TNF receptor-associated factor 2