Combination therapies and novel delivery systems: a new frontier in overcoming TRAIL resistance in gastric cancer.

Gastric cancer (GC) presents a formidable challenge in oncology, mainly due to its inherent resistance to therapies such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). This review delineates the multifaceted mechanisms underlying TRAIL resistance in GC, encompassing the deregulation of death receptors (DRs) and decoy receptors (DcRs), aberrant signaling pathways, and the influence of the tumor microenvironment (TME). Innovative strategies such as nanoparticle-based drug delivery systems and oncolytic viral therapies are being explored to counteract these challenges. Nanoparticles enhance TRAIL delivery and efficacy by exploiting the enhanced permeability and retention (EPR) effect, while oncolytic viruses can selectively target cancer cells and stimulate immune responses. Combination therapies, integrating TRAIL with conventional chemotherapeutics like paclitaxel, cisplatin, and 5-fluorouracil, have shown promise in overcoming resistance by modulating apoptotic pathways and downregulating multidrug resistance genes. Additionally, novel agents like cyclopamine, decitabine, and genistein have emerged as effective TRAIL sensitizers by modulating apoptotic pathways and enhancing DR5 expression. Furthermore, the integration of epigenetic modifiers can restore TRAIL sensitivity by demethylating DR4 and DR5 genes. This review emphasizes the need for a comprehensive understanding of the molecular underpinnings of TRAIL resistance and the potential of combination therapies and TRAIL delivery by nanoparticles and oncolytic viruses to enhance treatment outcomes in GC. Future research should focus on elucidating predictive biomarkers and optimizing therapeutic regimens to improve the clinical efficacy of TRAIL-based strategies in GC.