Hereafter, we will discuss general characteristics of therapy-induced reprogramming in cancer phenotypes with a focus on IFN signalling and epigenetic remodelling, before focusing on the H3K9me3-specific histone methyltransferases SETDB1 and SETDB2 and their detailed role (s) in biology and the development of adaptive drug-tolerance in these aforementioned phenotypes. The gene discussed is SETDB2; the disease is cancer.