Molecular mechanisms of tumor resistance to radiotherapy

Abstract

Background: Cancer is the most prevalent cause of death globally, and radiotherapy is considered the standard of care for most solid tumors, including lung, breast, esophageal, and colorectal cancers and glioblastoma. Resistance to radiation can lead to local treatment failure and even cancer recurrence.

Main body: In this review, we have extensively discussed several crucial aspects that cause resistance of cancer to radiation therapy, including radiation-induced DNA damage repair, cell cycle arrest, apoptosis escape, abundance of cancer stem cells, modification of cancer cells and their microenvironment, presence of exosomal and non-coding RNA, metabolic reprogramming, and ferroptosis. We aim to focus on the molecular mechanisms of cancer radiotherapy resistance in relation to these aspects and to discuss possible targets to improve treatment outcomes.

Conclusions: Studying the molecular mechanisms responsible for radiotherapy resistance and its interactions with the tumor environment will help improve cancer responses to radiotherapy. Our review provides a foundation to identify and overcome the obstacles to effective radiotherapy.

Keywords: Cancer; Radiotherapy; Tumor resistance.

Fig. 1

The multiple pathways for DNA damage repair, cell cycle arrest, and apoptosis escape after radiation therapy. Key regulators in the DNA damage repair pathway may alter sensitivity to radiotherapy in cancer cells, whereas cell cycle checkpoints may respond to damage when tumor cells are exposed to ionizing radiation, thus causing cell cycle arrest and allowing more time for repair, which increases resistance to radiotherapy. If DNA damage repair is unsuccessful, apoptotic signaling pathways are induced to resist radiotherapy damage. HR: homologous recombination, NHEJ: non-homologous end joining, BER: base excision repair DSBs: double-strand breaks, SSBs: single-strand breaks, ATM: ataxia-telangiectasia mutated, ATR: ATM and Rad3-related kinase, DNA-PKcs: DNA-dependent protein kinase, MRN: Mre11–Rad50–NBS1, RPA: replication protein A, DNA-PKcs: DNA-dependent protein kinase catalytic subunit, CHK1: checkpoint kinase 1, CHK2: checkpoint kinase 2, PARP: poly(ADP-ribose) polymerase, XRCC4: X-ray repair cross-complementing protein 4, XLF:XRCC4-like factor, PAXX: Paralogue of XRCC4 and XLF, LIG4: DNA ligase IV, MDC1: mediator of DNA damage checkpoint protein 1, CAD: caspase-activated DNase, ICAD: inhibitor of CAD, MDM2: mouse double minute 2 homolog, FBXW7: F-box and WD repeat domain-containing 7, BCL-2: B-cell lymphoma 2

Fig. 2

The development of radioresistance in the tumor microenvironment after radiation. Radiation can induce hypoxia, fibrosis, vascular damage, chronic inflammation, and immunosuppression in the tumor microenvironment, all of which may lead to RT resistance. Cancer-associated fibroblasts are also important aspects of the tumor microenvironment for the generation of radioresistance because they affect immune cells in such a way that leads to immunosuppression, fibrosis, and extracellular matrix remodeling. RT: radiation therapy, ROS: reactive oxygen species, GSH: glutathione, VEGF: vascular endothelial growth factor, Treg: regulatory T cells, NK: natural killer cells, DC: dendritic cells, CAF: tumor-associated fibroblasts, MDSCs: bone-marrow-derived suppressor cells, ECM: extracellular matrix, IL-1α: interleukin-1α, HIF-1α: hypoxia-inducible factor 1α, PDGF: Platelet-derived growth factor, CSC: Cancer stem cell, NADPH: nicotinamide adenine dinucleotide phosphate oxidase, TGF-β: transforming growth factor-β, CHK1: checkpoint kinase 1, CHK2: checkpoint kinase 2, cGAS: cyclic GMP-AMP synthase, STING: stimulator of interferon genes, IFN: interferon, PD‑L1: programmed cell death 1 ligand 1, IL‑10: interleukin 10, ICD: immunogenic cell death

Fig. 3

The mechanisms by which cancer stem cells generate radioresistance. This diagram shows how CSCs can self-renew upon differentiation, become quiescent, be involved in tumorigenesis, and generate immunosuppressive signals as well as exert possible effects of DNA damage repair, low ROS levels, apoptosis, autophagy, and epithelial–mesenchymal transitions in tumor stem cell–associated radioresistance. In addition, several active signaling pathways (e.g., Wnt Notch Hedgehog TGF-ß PI3K/AKT/mTOR) may also be closely related to tumor stem cell radioresistance. EMT: epithelial–mesenchymal transition, ROS: reactive oxygen species, TGF-β: transforming growth factor-β, PD-L1: programmed cell death ligand 1, IL-10: interleukin 10, Bcl-2: B-cell lymphoma-2

Fig. 4

The relationship between metabolic reprogramming and radioresistance. Active glycolysis and lipid metabolism, which are typical of cancer metabolism, promote the development of radioresistance by mediating the development of immunosuppressive microenvironments and blocking apoptosis. In addition, the high expression of glutamine synthetase, purines, and serine protease inhibitor E2 can promote DNA damage repair, thereby leading to radioresistance. FAO: fatty acid oxidation, FFA: free fatty acid, Glu; glucose, G6P: glucose-6-phosphate, G3P: glyceraldehyde triphosphate, DHAP: dihydroxyacetone phosphate, FBP: fructose-1,6-bisphosphate, GS: glutamine synthetase, ATM: ataxia-telangiectasia mutated, NF-κB: nuclear factor-kappa B, Cyt c: cytochrome c, HK2: hexokinase 2, PFK1: phosphofructokinase 1, MDSCs: myeloid-derived suppressor cells, DHAP: dihydroxyacetone phosphate, HIF-1α: hypoxia-inducible factor 1α, SERPINE2: serine protease inhibitor E2, TCA cycle: tricarboxylic acid cycle

Fig. 5

The role of exosomes in cancer radiotherapy resistance. Radiation-induced paracrine effects mediated by exosomes and their contents (e.g., exosomal proteins and non-coding RNAs) affect radiotherapy efficacy via different pathways. Radiation also promotes the polarization of M1 tumor-associated macrophages to the M2 phenotype, which suppresses the anti-tumor immune response, whereas M1 macrophage–derived exosomes repolarize the M2 phenotype to the M1 phenotype, reshaping the tumor immunosuppressive microenvironment and improving the efficacy of radiation therapy. M1: M1-type tumor-associated macrophages (anti-tumor), M2: M2-type tumor-associated macrophages (pro-tumor), miRNAs: micro-RNAs, lncRNAs: long non-coding RNAs, circRNA: circular RNA, mRNA: messenger RNA

Fig. 6

Pathways promoting iron-caused death, PUFA-PL synthesis, the GPX4 and FSP1-CoQ signaling axes, and iron metabolism. Iron-caused death facilitates increased radiosensitivity (high expression in the blue areas), and inhibition of iron-caused death helps cancer cells acquire radioresistance (high expression in the purple areas). ACSL4: acyl coenzyme A synthetase long chain family member 4, LPCAT3: lysophosphatidylcholine acyltransferase 3, POR: cytochrome P450 oxidoreductase, ATM: ataxia-telangiectasia mutated, FSP1: ferroptosis suppressor protein 1, Cys: cysteine, GSH: glutathione, GPX4: glutathione peroxidase 4, PUFA-PL: polyunsaturated fatty acid- containing phospholipid, ROS: reactive oxygen species, CoQ: ubiquinone, SLC7A11: solute carrier family 7 member 11, LPCAT3: lysophosphatidylcholine acyltransferase 3, SLC3A2: Solute Carrier Family 3 member 2, PUFA: polyunsaturated fatty acid, CoQH2: ubiquinol, ALOX: lipoxygenase