We describe a TNF fusion protein designated TNF-Selectokine, which is a homo-trimeric molecule comprised of a single chain antibody (scFv) targeting module, a trimerization domain and TNF. TNF-Selectokine exerts high bioactivity towards the targeted and adjacent, antigen negative cells. Membrane targeting dependent immobilization of the TNF-Selectokine induced cell death in TNFR1 and TNFR2 dependent manner, thus cell bound TNF-Selectokine mimicks membrane TNF. To restrict TNF activity to the tumor, a prototype of a TNF-Selectokine prodrug was constructed by insertion of a TNFR1 fragment, separated from TNF by a protease-sensitive linker. The prodrug exerts minimal TNF activity, but can be activated in vitro several thousand-fold by proteolytic digest, showing the principal feasibility of this approach. Choice of cleavage site(s) recognized by protease(s) typically associated with a given carcinoma should allow high dose systemic application of the respective TNF prodrug that unveils its specific bioactivity only in targeted tissues.