Revisiting the role of TRAIL/TRAIL-R in cancer biology and therapy

TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, can induce apoptosis in cancer cells, sparing normal cells when bound to its associated death receptors (DR4/DR5). This unique mechanism makes TRAIL a potential anticancer therapeutic agent. However, clinical trials of recombinant TRAIL protein and TRAIL receptor agonist monoclonal antibodies have shown disappointing results due to its short half-life, poor pharmacokinetics and the resistance of the cancer cells. This review summarizes TRAIL-induced apoptotic and survival pathways as well as mechanisms leading to apoptotic resistance. Recent development of methods to overcome cancer cell resistance to TRAIL-induced apoptosis, such as protein modification, combination therapy and TRAIL-based gene therapy, appear promising. We also discuss the challenges and opportunities in the development of TRAIL-based therapies for the treatment of human cancers.