In conclusion, our data highlight the complexity of targeting hexavalent TRAIL molecules to tumor cells for increased cytotoxicity, but also show that by careful selection of a tumor-targeting antibody it should be possible to further improve the anti-tumoral activity of a priori powerful hexavalent Fc-scTRAIL molecules in order to achieve lasting, complete tumor remissions. Here, TNFSF10 is linked to neoplasm.