Paradoxically, more than 20 years later, targeting the TNF/TNF-R and CD95/CD95L system has become attractive for cancer therapy again, however, with the opposing pharmacological concept, as blockade of TNF or appears to exert therapeutic benefit in certain malignancies.99, 100 In contrast, targeting of the TRAIL/TRAIL-R system has so far focused on inducing a death signal in tumor cells and different TRAs have been developed and already undergone first clinical testing (Figure 4). Here, TNF is linked to cancer.