The multifaceted role of TRAIL signaling in cancer and immunity

Tumor necrosis factor (TNF)‐related apoptosis‐inducing ligand (TRAIL) is a member of the TNF superfamily that can lead to the induction of apoptosis in tumor or infected cells. However, activation of TRAIL signaling may also trigger nonapoptotic pathways in cancer and in nontransformed cells, that is, immune cells. Here, we review the current knowledge on noncanonical TRAIL signaling. The biological outcomes of TRAIL signaling in immune and malignant cells are presented and explained, with a focus on the role of TRAIL for natural killer (NK) cell function. Furthermore, we highlight the technical difficulties in dissecting the precise molecular mechanisms involved in the switch between apoptotic and nonapoptotic TRAIL signaling. Finally, we discuss the consequences thereof for a therapeutic manipulation of TRAIL in cancer and possible approaches to bypass these difficulties.