Significance CD137 (4-1BB) is a target for tumor immunotherapy, which has been pursued in clinical trials with agonist antibodies or the natural ligand (CD137L). Liver toxicity is a serious dose-limiting problem that may be circumvented by selective functional or physical targeting to the tumor microenvironment. A CD137 agonist antibody prodrug that is preferentially activated by tumor-associated proteases constitutes an appealing way to enhance safety while preserving efficacy.