**5. Perspectives on the future use of exosomes in radiation therapy**

Radiation induces oxidative stress in host cells [8], and the RIBE induced by exosomes has been investigated in several studies. It has been reported that irradiated cells release more exosomes than non-irradiated cells [12, 76, 77]. Arscott et al. identified a relationship between increased secretion of exosomes and overexpression or mutation of p53 in glioblastoma cells [78]. Furthermore, it has been found that exosomes derived from irradiated cells are taken up by neighboring cells in greater numbers than those derived from non-irradiated cells [79]. Hazawa et al. suggested that one reason for this difference could be the enhancement of cellular attachment to exosomes via augmented formation of the CD29/CD81 complex induced by radiation [80]. Thus, the influence of irradiation is transferred to neighboring cells via interaction with exosomal cargo. Although, the mechanism via which cargo is included in exosomes is not clearly understood, exosomal expression of miRNA influences the effect of irradiation on cells [79, 81]. Nakaoka et al. also investigated this effect and found that exosomes derived from irradiated MIAPaCa-2 human pancreatic cancer cells induced a radiosensitive effect on neighboring cells through an increase in levels of reactive oxygen species in cells [79], which they attributed to a reduction in expression of antioxidant enzymes via changes in the miRNA profile in exosomes. A summary of the molecules involved in RIBE is presented in **Table 1**.

Radiation therapy can have profound immune-stimulatory effects and is increasingly viewed as a promising partner in combination therapy for patients receiving immunotherapy. Intrinsic events in cancer cells induced by DNA damage are central to the immune-modifying effects of radiation therapy [82]. These events have been investigated in studies of the DNA damage response, which focuses on the tumor microenvironment. In addition to its ability to destroy cancer cells by damaging DNA,


**Table 1.**

*Radiation-induced bystander effect induced by exosomes.*

#### **Figure 3.**

*Radiation and immune response via cancer-derived exosomes in the tumor microenvironment. The pathway related to activation of cytoplasmic nucleic acid sensors. Tumor-derived exosomes can transport type I IFNstimulatory dsDNA from irradiated cancer cells to dendritic cells via the STING pathway. T-cells produce IFN-. Inhibition of activation of CD8-positive T-cells by PD-1/L1 binding. cGAS cytoplasmic DNA-sensing cyclic GMP-AMP synthase; dsDNA, double-stranded DNA; IFN, interferon; STING, stimulator of interferon genes.*

radiation therapy can modulate both the immunotherapy and adjuvant therapy of tumors by triggering the release of pro-inflammatory mediators, increasing tumorinfiltrating immune-stimulatory cells. and enhancing the expression of neoantigens [82–84] and immune-stimulatory signaling by cyclic dinucleotide cyclic GMP-AMP. Understanding the mechanistic basis of radiation therapy as an anticancer treatment has been transformed by the recent discovery that DNA damage in cycling cancer cells can activate cytoplasmic nucleic acid sensors [82, 83]. The cGAS (cytoplasmic DNAsensing cyclic GMP–AMP synthase)-STING (stimulator of interferon genes) pathway is involved in this process [85, 86]. Using this pathway, tumor-derived exosomes can shuttle TREX1-sensitive type I interferon-stimulatory double-stranded DNA from irradiated cancer cells to dendritic cells (**Figure 3**) [87].
