TRAIL in oncology: From recombinant TRAIL to nano- and self-targeted TRAIL-based therapies

[Display omitted] TNF-related apoptosis-inducing ligand (TRAIL) selectively induces the apoptosis pathway in tumor cells leading to tumor cell death. Because TRAIL induction can kill tumor cells, cancer researchers have developed many agents to target TRAIL and some of these agents have entered clinical trials in oncology. Unfortunately, these trials have failed for many reasons, including drug resistance, off-target toxicities, short half-life, and specifically in gene therapy due to the limited uptake of TRAIL genes by cancer cells. To address these drawbacks, translational researchers have utilized drug delivery platforms. Although, these platforms can improve TRAIL-based therapies, they are unable to sufficiently translate the full potential of TRAIL-targeting to clinically viable products. Herein, we first summarize the complex biology of TRAIL signaling, including TRAILs cross-talk with other signaling pathways and immune cells. Next, we focus on known resistant mechanisms to TRAIL-based therapies. Then, we discuss how nano-formulation has the potential to enhance the therapeutic efficacy of TRAIL protein. Finally, we specify strategies with the potential to overcome the challenges that cannot be addressed via nanotechnology alone, including the alternative methods of TRAIL-expressing circulating cells, tumor-targeting bacteria, viruses, and exosomes.