Ceramide-elevating therapy promotes protein kinase R (PKR) activation through direct binding to ceramide. This promotes the integrated stress response through phosphorylation of eukaryotic initiation factor 2 alpha, which activates the transcription factor ATF4. Subsequent expression of Noxa blocks antiapoptotic Mcl-1 to overcome resistance to the Bcl-2 inhibitor venetoclax. Professional illustration by Patrick Lane, ScEYEnce Studios.