Fig. 3

IR-induced side effects on cancer cells and the tumour microenvironment (TME). Radiotherapy has the paradoxical side-effect of increasing tumour aggressiveness. IR promotes ROS production in cancer cells, which may induce the activation of oncogenes and the inactivation of tumour suppressors, which further promote oncogenic metabolism. Metabolic alterations are involved in tumour progression, and include growth, invasion, metastasis, and the acquisition of the CSC phenotype, thereby contributing to tumour recurrence and distant metastasis. Given that IR induces EMT and CSC properties in cancer cells, it is possible that IR-induced oncogenic metabolism is required for the acquisition of the EMT and CSC phenotypes. IR can also elicit various changes in the TME, such as: 1) the emergence of cancer-associated fibroblasts (CAFs), activity-mediated extracellular matrix (ECM) remodelling, and fibrosis, 2) cycling hypoxia, and 3) an inflammatory response. IR activates cancer-associated fibroblasts (CAFs) to promote the release of growth factors, including transforming growth factor-β (TGF-β), and extracellular matrix (ECM) modulators, including matrix metalloproteinase (MMP). TGF-β directly affects tumour cells and CAFs, enhances tumour immune escape, and activates hypoxia-inducible factor-1 (HIF-1) signalling. MMPs degrade the ECM, facilitating tumour invasion and metastasis. IR can also cause damage to the vascular endothelial cells (EC), leading to hypoxia that further promotes HIF-1 signalling. HIF-1 increases the expression of vascular endothelial growth factor (VEGF) and chemokine (C-X-C motif) ligand 12 (CXCL12), both of which induce angiogenesis and vasculogenesis. IR also upregulates integrins on ECs that enhance survival and confer radioresistance. Although IR activates an antitumour immune response, this signalling is frequently suppressed by tumour escape mechanisms (such as programmed cell death protein 1 ligand 1 [PDL1] signalling) and by suppressive immune cells (regulatory T cells [Treg], myeloid-derived suppressor cells [MDSC], and tumour-associated macrophages [TAM]), which are relatively less radiosensitive than other lymphocyte subsets. These IR-mediated changes in the TME may constitute additional adverse effects of IR on the patient by promoting angiogenesis, invasion, metastasis, and radioresistance