Rodrigues Paul, Ahmed Abdulrahman T, Jabir Majid, Rasool Khetam Habeeb, Menon Soumya V, Sharma Aryantika, Kumar M Ravi, Al-Sabti Matheel D, Jawad Sabrean F, Al-Abdeen Salah Hassan Zain
Department of Science, King Khalid University, Al-Faraa, Saudi Arabia.
College of Nursing, University of Al-Maarif, Al-Anbar, 31001, Iraq.
Naunyn Schmiedebergs Arch Pharmacol. 2025 May 10. doi: 10.1007/s00210-025-04208-6.
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.
胃癌（GC）在肿瘤学领域构成了巨大挑战，主要是因为其对诸如肿瘤坏死因子相关凋亡诱导配体（TRAIL）等疗法具有内在抗性。本综述阐述了GC中TRAIL抗性的多方面机制，包括死亡受体（DRs）和诱饵受体（DcRs）的失调、异常信号通路以及肿瘤微环境（TME）的影响。正在探索基于纳米颗粒的药物递送系统和溶瘤病毒疗法等创新策略来应对这些挑战。纳米颗粒通过利用增强的通透性和滞留（EPR）效应来增强TRAIL的递送和疗效，而溶瘤病毒可以选择性地靶向癌细胞并刺激免疫反应。将TRAIL与紫杉醇、顺铂和5-氟尿嘧啶等传统化疗药物联合使用的联合疗法，在通过调节凋亡途径和下调多药耐药基因来克服抗性方面已显示出前景。此外，环杷明、地西他滨和染料木黄酮等新型药物已成为有效的TRAIL增敏剂，通过调节凋亡途径和增强DR5表达来实现。此外，表观遗传修饰剂的整合可以通过使DR4和DR5基因去甲基化来恢复TRAIL敏感性。本综述强调需要全面了解TRAIL抗性的分子基础，以及联合疗法以及纳米颗粒和溶瘤病毒递送TRAIL以提高GC治疗效果的潜力。未来的研究应专注于阐明预测性生物标志物并优化治疗方案，以提高基于TRAIL的策略在GC中的临床疗效。
