Basic and applied research progress of TRAIL in hematologic malignancies

Abstract

Hematological malignancies encompass a diverse range of blood-related cancers characterized by abnormal blood cell production. These cancers, classified by the World Health Organization based on lineage, cell origin, and progression, provide a more comprehensive framework for understanding cancer biology. This classification has significantly advanced cancer research, particularly in genetic analyses for diagnosis and treatment. Despite recent clinical improvements, challenges, such as relapse, resistance, and high mortality, remain unresolved. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a protein that induces apoptosis in cancer cells without affecting normal cells, has emerged as a promising therapeutic target. However, its clinical efficacy is limited by factors, such as tumor heterogeneity and resistance to TRAIL signaling. This review examines the mechanisms of TRAIL in hematological malignancies, factors contributing to resistance, and the current state of preclinical and clinical research, highlighting potential strategies to enhance TRAIL-based therapies in blood cancers.

Keywords: Clinical application; Drug tolerance; Hematologic malignancies; TRAIL.

Figure 1.

Pro-apoptotic TRAIL signaling pathway. The TRAIL signaling pathway triggers apoptosis by binding to its receptors, forming the DISC. In type I cells, DISC formation activates caspase 8, initiating a complete caspase cascade, and inducing apoptosis. In type II cells, caspase 8 activation alone is insufficient due to inhibition by XIAP. To overcome this, caspase 8 cleaves BID, which activates BAX and BAK in the mitochondria, causing MOMP. MOMP releases SMAC, which relieves the inhibition of caspases by XIAP, allowing full caspase activation. Additionally, released cytochrome c forms an apoptosome with APAF1, activating caspase 9. This cascade enhances caspase 3 activation, leading to apoptosis. APAF1 = apoptotic protease activating factor 1, BID = BH3-interacting domain death agonist, DISC = death-inducing signaling complex, MOMP = mitochondrial outer membrane permeabilization, SMAC = second mitochondria-derived activator of caspases, tBID = truncated state of BID, TRAF = TNF receptor-associated factor, TRAIL = tumor necrosis factor-related apoptosis-inducing ligand, XIAP = X-linked inhibitor of apoptosis protein.

Figure 2.

Schematic of various approaches to TRAIL-based cancer therapy. TRAIL proteins are conjugated with different moieties, including nanoparticles, to improve encapsulation efficiency, targeting specificity, and stability in the physiological environment. CRISPR/Cas9 gene editing is used to enhance TRAIL expression in tumor cells or modify mesenchymal stem cells for cell-based therapy. Gene therapy involves delivering TRAIL-encoding genes directly to cancer cells. This can be achieved by modifying cells to express TRAIL for therapeutic effects. TRAIL derivatives and antibodies are designed to improve receptor binding and induce apoptosis in a wider range of tumor cells. Combination therapy strategies incorporate TRAIL with chemotherapeutic agents or DNA/RNA-based therapeutics, enhancing synergistic anti-cancer activity. TRAIL = tumor necrosis factor-related apoptosis-inducing ligand.