Singh, DeepikaTewari, MallikaSingh, SunitaNarayan, Gopeshwar2025-01-302025-01-30202114796694https://dl.bhu.ac.in/ir/handle/123456789/25405TNF-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. � 2021 Future Medicine Ltdapoptosiscancer therapyclinical trialsdeath receptorsdecoy receptorsgene therapyresistanceTNFRSF superfamilyTRAILTRAIL-RReviewhttps://doi.org/10.2217/fon-2020-0727