Conclusively, one can wonder how cells triage this scenario of the interaction between complex DNA damage, immune signaling and systemic effects, which is the most important in regulating the overall outcome of this complex crosstalk (Figure 2). It is rather secure to suggest that complex and persistent DNA damage constitutes a major “danger” signal for the cells and this probably alarms the whole cell or tissue about something “peculiar” happening in this area of damage. If this complex form of damage is processed correctly and all problems have been resolved then the alarm goes off, but the “danger” signaling may already have generated an immune response. In this case, the outcome is uncertain. Immune response manifested initially at least as innate and later on as adaptive and inflammation maybe present, especially when specific “danger” signals are produced due to cell death or senescence. As so, a continuing systemic effect of unknown severity and duration will be induced resulting to a chronic state of immune response and a precursor of pathological evolution and disease as presented with red in Figure 2. Recent evidence obtained using mice carrying an ERCC1-XPF DNA repair defect systematically or in adipocytes, suggests that persistent DNA damage-driven autoinflammation plays a causative role in adipose tissue degeneration, with important complications for advanced lipodystrophies and aging . In any case, the knowledge of the exact mechanisms and mediators of systemic responses will be very useful in various applications that involve complex DNA damage formation, such as RT, chemotherapy and tumor growth early detection. As nicely presented in a recent work by Pateras et al. continuous triggering of DDR/R can lead to excessive innate and adaptive immune response which, in turn, can lead to pathological conditions and disease .