Hematologic malignancies such as leukemia, lymphoma, and multiple myeloma remain among the most challenging cancers to treat due to high relapse rates and treatment resistance. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a unique member of the TNF superfamily, has emerged as a promising therapeutic candidate due to its ability to selectively induce apoptosis in cancer cells while sparing normal tissues. In a comprehensive review recently published in Blood Science，researchers examine the molecular mechanisms of TRAIL signaling, resistance pathways, and evolving therapeutic strategies in blood cancers.Mechanisms of TRAIL-Induced Apoptosis
（Blood Science. 7(2):e00221, June 2025.）
TRAIL is a type II transmembrane protein that initiates apoptosis by binding to its cognate death receptors DR4 and DR5. This interaction leads to the assembly of the death-inducing signaling complex (DISC), which activates initiator caspase-8 and subsequently the executioner caspase-3 cascade. In type II tumor cells, mitochondrial amplification is required, involving BID cleavage and the activation of BAX and BAK. This culminates in the release of cytochrome C and caspase-9 activation, further driving apoptosis. Regulatory proteins, including FLIP, Bcl-2, and XIAP, interfere at various points in the cascade and contribute significantly to TRAIL resistance. Understanding the intricacies of this signaling axis is essential for developing targeted TRAIL-based therapies.
TRAIL and Immune Regulation in Blood Cancers
Beyond its direct cytotoxic function, TRAIL plays a vital immunomodulatory role in hematologic malignancies. It is secreted by natural killer (NK) cells and cytotoxic T lymphocytes and contributes to immune-mediated tumor surveillance. TRAIL also influences the differentiation and homeostasis of hematopoietic stem and progenitor cells. In acute myeloid leukemia (AML), elevated TRAIL expression is associated with reduced disease burden in preclinical models. Additionally, TRAIL modulates the tumor microenvironment by affecting cytokine secretion and stromal cell behavior, potentially enhancing antitumor immunity in the bone marrow niche.
Therapeutic Potential and Combination Strategies
Several TRAIL-based agents have been evaluated in hematologic cancers, including recombinant TRAIL proteins like dulanermin and agonistic antibodies targeting TRAIL receptors such as mapatumumab and conatumumab. In AML and chronic lymphocytic leukemia (CLL), TRAIL shows synergy with histone deacetylase inhibitors and PI3K/Akt pathway inhibitors, both of which enhance death receptor expression. In multiple myeloma, TRAIL monotherapy has limited efficacy, but proteasome inhibitors (e.g., bortezomib) and IL-6 pathway inhibitors have demonstrated the ability to overcome resistance and restore sensitivity in preclinical settings.
Mechanisms of Resistance to TRAIL Therapy
Clinical translation of TRAIL therapies has been hindered by intrinsic and acquired resistance. Key resistance mechanisms include downregulation or mutation of DR4/DR5, deficiencies in DISC components such as FADD and caspase-8, and overexpression of anti-apoptotic proteins including FLIP, Bcl-xL, and XIAP. Mitochondrial defects that impair BID activation or cytochrome C release also contribute. Moreover, hyperactivation of prosurvival pathways such as NF-κB and PI3K/Akt suppresses TRAIL-mediated cell death. These multifactorial resistance patterns underscore the need for multi-targeted combination approaches.
Emerging Strategies to Overcome Resistance
Recent research is focused on overcoming resistance through innovative techniques. Combination regimens incorporating chemotherapeutics, kinase inhibitors, and immune checkpoint modulators have shown promise. Gene editing tools like CRISPR/Cas9 are being explored to upregulate TRAIL receptors or knock out resistance genes. Nanoparticle delivery systems for TRAIL proteins or DNA encoding TRAIL have improved pharmacokinetics and tumor targeting. Moreover, small-molecule TRAIL mimetics with enhanced systemic stability are currently in development, offering new therapeutic avenues with better clinical potential.
Conclusion and Future Perspectives
TRAIL represents a compelling therapeutic avenue for hematologic malignancies, offering dual benefits of tumor-selective apoptosis and immune modulation. While resistance and delivery challenges persist, ongoing innovations in delivery systems, gene editing, and rational combination therapies are paving the way for more effective clinical applications. As highlighted in the Blood Science review by Professor Zhang and colleagues, a deeper mechanistic understanding and translational research are essential to fully unlock the clinical potential of TRAIL in leukemia, lymphoma, and myeloma. The future of TRAIL-based treatment may lie in personalized regimens tailored to overcome specific resistance pathways in each patient.
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