Figure 2: TNF/TNFR signaling and TNFR-targeted therapeutics. (a) TNFR1 and TNFR2 are effectively activated by membrane TNF, but sTNF can only trigger TNFR1-signaling. (b) TNFR-targeted drugs include a stabilized TNFR2-selective scTNF that may help to induce TNFR1 proapoptotic signaling, as well as targeted strategies such as scFv:sTNFL, and scFv:sTNF-TNFR1 prodrug constructs. The latter only become activated after target antigen-selective binding and subsequent cleavage of the TNFR1 inhibitory domain by tumor-overexpressed proteases.