Morbidity and mortality are often caused by cancer. It is an ongoing challenge for science, even though the “war on cancer“ to develop cures for this scourge of humanity began in 1971, when then U.S. president Nixon signed the National Cancer Act. Since then, progress has been made in the field of targeted therapies and in understanding how cancer cells work. Today, NK-based immunotherapies in particular are an emerging field of interest in cancer research. NK cells play an important role as part of the innate immune system, as they have potent cytolytic activity against tumors. Moreover, NK cells can mediate cytotoxicity via apoptotic pathways through FasL or TRAIL signaling. Similar to FasL, TRAIL is a death ligand belonging to the TNF superfamily that can induce cell death and inflammation by activation of its cognate receptors. Yet, although these two different receptors share most of the components that act in their respective signaling pathways downstream of ligand-induced receptor activation, TRAIL is well tolerated when applied systemically whilst FasL is highly toxic when applied in the same way. The good tolerability of TRAIL combined with its selective capacity to induce cell death in tumor cells made TRAIL a promising candidate in cancer therapy. However, clinical trials testing Dulanermin, a soluble pharmacological version of recombinant TRAIL, did not provide therapeutic benefit in several clinical trials. The general aim of my project is to decipher the mechanism that modulates the release of soluble TRAIL and its possible implication as a tumor cytoprotective event during cancer development.