Shirzadian Mohsen, Moori Sepideh, Rabbani Reza, Rahbarizadeh Fatemeh
Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
Front Immunol. 2025 Apr 16;16:1545270. doi: 10.3389/fimmu.2025.1545270. eCollection 2025.
Cancer immunotherapy has been transformed by chimeric antigen receptor (CAR) T-cell treatment, which has shown groundbreaking results in hematological malignancies. However, its application in solid tumors remains a formidable challenge due to immune evasion, tumor heterogeneity, and safety concerns arising from off-target effects. A long-standing effort in this field has been the development of synthetic receptors to create new signaling pathways and rewire immune cells for the specific targeting of cancer cells, particularly in cell-based immunotherapy. This field has undergone a paradigm shift with the introduction of synthetic Notch (synNotch) receptors, which offer a highly versatile signaling platform modeled after natural receptor-ligand interactions. By functioning as molecular logic gates, synNotch receptors enable precise, multi-antigen regulation of T-cell activation, paving the way for enhanced specificity and control. This review explores the revolutionary integration of synNotch systems with CAR T-cell therapy, emphasizing cutting-edge strategies to overcome the inherent limitations of traditional approaches. We delve into the mechanisms of synNotch receptor design, focusing on their ability to discriminate between cancerous and normal cells through spatiotemporally controlled gene expression. Additionally, we highlight recent advancements to improve therapeutic efficacy, safety, and adaptability in treating solid tumors. This study highlights the potential of synNotch-based CAR-T cells to transform the field of targeted cancer therapy by resolving present challenges and shedding light on potential future paths.
嵌合抗原受体(CAR)T细胞疗法已经改变了癌症免疫疗法,该疗法在血液系统恶性肿瘤中显示出了突破性的成果。然而,由于免疫逃逸、肿瘤异质性以及脱靶效应引发的安全性问题,其在实体瘤中的应用仍然是一项艰巨的挑战。该领域长期以来的一项努力是开发合成受体,以创建新的信号通路并重塑免疫细胞,使其能够特异性靶向癌细胞,尤其是在基于细胞的免疫疗法中。随着合成Notch(synNotch)受体的引入,该领域发生了范式转变,synNotch受体提供了一个高度通用的信号平台,其基于天然受体-配体相互作用建模。通过充当分子逻辑门,synNotch受体能够对T细胞激活进行精确的多抗原调控,为提高特异性和可控性铺平了道路。本综述探讨了synNotch系统与CAR T细胞疗法的革命性整合,强调了克服传统方法固有局限性的前沿策略。我们深入研究了synNotch受体的设计机制,重点关注其通过时空控制基因表达来区分癌细胞和正常细胞的能力。此外,我们突出了在提高实体瘤治疗的疗效、安全性和适应性方面的最新进展。这项研究强调了基于synNotch的CAR-T细胞通过解决当前挑战并为未来潜在路径提供启示来改变靶向癌症治疗领域的潜力。