Molecular mechanisms of tumor resistance to radiotherapy

Table 1 Mechanisms of cancer cell resistance to radiotherapy

Mechanisms	Mediators	References
DNA damage repair	ATM DNA-PKcs PARPs rH2AX WEE1 BRCA1 MDC1 53BP1 NBS1/hMRE11/hRAD50 Ku70/Ku80	[12,13,14,15,16,17,18,19,20,21]
Cell cycle redistribution	ATM ATR Chk1 Chk2 P53 P21	[22,23,24,25,26,27,28,29,30,31]
Apoptosis escape	Bcl family Pro-survival pathways IAPs	[32,33,34]
Microenvironment	Hypoxia	[33]
	Inflammation	[35]
	Immunosuppression	[36,37,38,39,40,41,42,43,44,45,46,47,48,49,50]
	Cancer-associated fibroblast	[51,52,53,54,55,56,57,58,59,60,61,62,63]
CSCs	High survival (autophagy, apoptosis, DNA damage repair)	[64, 65]
	Generates immunosuppressive signal	[44]
	Low ROS levels	[66, 67]
	Epithelial–mesenchymal transition (high plasticity)	[68]
	Quiescence	[69]
	Signaling pathway (Wnt Notch Hedgehog TGF-ß PI3K/AKT/mTOR)	[37,38,39, 70, 71]
Metabolic reprogramming	Glucose metabolism	[72, 73]
	Lipid metabolism	[74,75,76]
	High expression of glutamine synthetase, purine, and serine protease inhibitor E2	[77,78,79]
Exosomes	M1-M2 TAM polarization	[80]
	ncRNA	[81,82,83,84,85,86]
Ferroptosis	GPX4 PUFA-PL CoQ-FSP1 Iron metabolism	[87,88,89,90]

ATM ataxia-telangiectasia mutated, DNA-PKcs DNA-dependent protein kinase catalytic subunit, CHK1 checkpoint kinase 1, CHK2 checkpoint kinase 2, PARP poly(ADP-ribose) polymerase, ATR ATM and Rad3-related kinase, DNA-PKcs DNA-dependent protein kinase, IAPs Inhibitor of apoptosis proteins, M1 M1-type tumor-associated macrophages (anti-tumor), M2 M2-type tumor-associated macrophages (pro-tumor), GPX4 glutathione peroxidase 4, PUFA-PL polyunsaturated fatty acid- containing phospholipid, ROS reactive oxygen species, BRCA1 Breast Cancer Susceptibility Protein-1, MDC1 mediator of DNA damage check point protein 1, BRCA1 Breast Cancer Susceptibility Protein-1

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