Unfortunately, melanoma cells were shown to stay largely resistant against conventional TRAIL treatment.8,9 Importantly, conventional trimeric TRAIL and receptor-agonistic antibodies as single agents failed in clinical trials, due to the limited therapeutic activity in patients.10 To overcome this therapeutic limitation we have developed novel second-generation TRAIL receptor-targeted agonists, with increased bioactivity enhancing the cytotoxic capacity towards cancer cells. Here, TNFSF10 is linked to melanoma.