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 non-apoptotic pathways in cancer and in non-transformed cells, i.e. immune cells. Here, we review the current knowledge on non-canonical TRAIL signaling. The biological outcomes of TRAIL signaling in immune and malignant cells is 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 non-apoptotic TRAIL signaling. Finally, we discuss the consequences thereof for a therapeutic manipulation of TRAIL in cancer and possible approaches to bypass these difficulties