TRAIL on trial: preclinical advances in cancer therapy

•TRAIL is able to induce apoptosis in a wide range of cancers.•TRAIL has been functionalized to diversify its traditional tumor-killing role.•Strategies to facilitate its deployment are discussed.•We provide a perspective for improving prospects of clinical implementation.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand, or TRAIL, is a promising anticancer agent as it can induce apoptosis in a wide range of cancers whilst generally sparing non-malignant cells. However, the translation of TRAIL into the clinic has been confounded by its short half-life, inadequate delivery methods, and TRAIL-resistant cancer cell populations. In this review, we discuss how TRAIL has been functionalized to diversify its traditional tumor-killing role and novel strategies to facilitate its effective deployment in preclinical cancer models. The successes and failures of the most recent clinical trials using TRAIL agonists are highlighted and we provide a perspective for improving its clinical implementation.