The three barriers senescent tumor cells must overcome to relapse.

Tumor cells that enter senescence as a response to treatment can be permanently arrested or removed by the immune system, resulting in a favorable patient outcomes. Alternatively, many studies have now shown that, in some tumors, the senescent program enables tumor cell survival, persistence, and eventually relapse, resulting in poor patient outcomes. Whether senescence is a positive or negative factor is dependent on whether on a clonal population of cells overcomes three critical barriers. First, senescence must enable survival from the initial stress of treatment, such as DNA damage, by preventing apoptosis and/or mitotic catastrophe. Senescent cells are also frequently immunogenic, thus, a second barrier is the activation of programs of immune evasion, such as PD-L1 expression, that outweigh the immunogenic properties. Third, senescent cells must escape their rigid arrest to proliferate again. Studies over the years have experimentally addressed challenging questions related to relapse and senescence, but more research is needed, particularly in vivo. Here, we discuss critical studies investigating how tumor cells that enter senescence as a response to treatment overcome barriers to relapse.