Figure 2: Cartoon illustrating some of the potential long-term fates of a tumor cell after undergoing ionizing radiation- (IR)-induced TCS. Cancer cells in TCS (blue square) can potentially: [1] remain in a permanently arrested state of TCS; [2] transition to a terminal/irreversible cell death pathway such as delayed apoptosis or autophagy; [3] eventually escape from TCS and recover the ability to proliferate (blue circle); [4] develop genetic instability, eventually generating highly malignant and/or therapy-resistant “giant” cells; [5] exert in-trans SASP-mediated effects on proliferating cancer cells, imparting a radioresistant phenotype on those cells (grey circle); such SASP-mediated effects can also be generated or reinforced by normal cells such as fibroblasts within the tumor microenvironment that have undergone IR-induced TCS, illustrated by the yellow circle/square (proliferating/TCS fibroblast); or [6] promote epithelial-mesenchymal transition (EMT) in normal cells (white circle) through their SASP secretion activity and thus drive the genesis of malignancy.