Triple kill: DDR inhibitors, radiotherapy and immunotherapy leave cancer cells with no escape.

Radiotherapy (RT) has been widely used in the clinical treatment of cancers, but radiotherapy resistance (RR) leads to RT failure, tumor recurrence and metastasis. Many studies have been performed on the potential mechanisms behind RR, and a strong link has been found between RR and DNA damage. RT-induced DNA damage triggers a protective mechanism called the DNA damage response (DDR). DDR consists of several aspects, including the detection of DNA damage and induction of cell cycle checkpoint, DNA repair, and eventual induction of cell death. A large number of studies have shown that DDR inhibition leads to significantly enhanced sensitivity of cancer cells to RT. DDR may be an effective target for radio- and chemo-sensitization during cancer treatment. Therefore, many inhibitors of important enzymes involved in the DDR have been developed, such as PARP inhibitors, DNA-PK inhibitors, and ATM/ATR inhibitors. In addition, DNA damage also triggers the cGAS-STING signaling pathway and the ATM/ATR (CHK)/STAT pathway to induce immune infiltration and T-cell activation. This review discusses the effects of DDR pathway dysregulation on the tumor response to RT and the strategies for targeting these pathways to increase tumor susceptibility to RT. Finally, the potential for the combination treatment of radiation, DDR inhibition, and immunotherapy is described.

Exosomes reveal the dual nature of radiotherapy in tumor immunology.

Radioresistance is the potential cause of cancer metastasis and recurrence. Radiation-induced changes in exosomes can partially explain the undesirable prognosis of radiotherapy (RT). Exosomes, newly discovered ways of cell communication, carry the characteristics of their origin, resulting in their diversity. Various exosomes in the tumor microenvironment exert different function in immune response. In this review, the dual effect of RT on the immune system was described, and the effect of radiotherapy on tumors via exosomes was explored. The molecules in exosomes after RT were described to play immunosuppressive and immunocompetent roles: immune-related receptors and cell signaling molecules involved in both adaptive and innate immune system were present. CD69, TIGIT, TIM-3, LAG-3 and the tumor necrosis factor (TNF) family that signal to T cells were shown to be regulated by exosomes after irradiation. The change in innate immunity-derived like receptors, Leukocyte Immunoglobin-Like Receptors (LILR) was described, as well as B7-H3, V-domain containing Ig suppressor of T cell activation (VISTA), and CD155 on tumor cells. These changed molecules inhibit and activate the immune system through different mechanisms. By analyzing the relationship between exosome-derived molecules and immunity, this review shows that radiotherapy can induce immunosuppression and immune clearance through exosomes, thereby treating tumors and improving patient prognosis.