Turn TRAIL Into Better Anticancer Therapeutic Through TRAIL Fusion Proteins.

Background: TNF-related apoptosis-inducing ligand (TRAIL) belongs to the tumor necrosis factor superfamily. TRAIL selectively induces apoptosis in tumor cells while sparing normal cells, which makes it an attractive candidate for cancer therapy. Recombinant soluble TRAIL and agonistic antibodies against TRAIL receptors have demonstrated safety and tolerability in clinical trials. However, they have failed to exhibit expected clinical efficacy. Consequently, extensive research has focused on optimizing TRAIL-based therapies, with one of the most common approaches being the construction of TRAIL fusion proteins.

Methods: An extensive literature search was conducted to identify studies published over the past three decades related to TRAIL fusion proteins. These various TRAIL fusion strategies were categorized based on their effects achieved.

Results: The main fusion strategies for TRAIL include: 1. Construction of stable TRAIL trimers; 2. Enhancing the polymerization capacity of soluble TRAIL; 3. Increasing the accumulation of TRAIL at tumor sites by fusing with antibody fragments or peptides; 4. Decorating immune cells with TRAIL; 5. Prolonging the half-life of TRAIL in vivo; 6. Sensitizing cancer cells to overcome resistance to TRAIL treatment.

Conclusion: This work focuses on the progress in recombinant TRAIL fusion proteins and aims to provide more rational and effective fusion strategies to enhance the efficacy of recombinant soluble TRAIL, facilitating its translation from bench to bedside as an effective anti-cancer therapeutic.