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REVIEW article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1545270
This article is part of the Research Topic Advances in Immune Cell Engineering for Treating Cancers and Other Diseases View all articles
SynNotch CAR-T cell, when synthetic biology and immunology meet again
Provisionally accepted- 1 Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Alborz, Iran
- 2 Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Alborz, Iran
- 3 Department of Stem Cell Technology and Tissue Engineering, Faculty of Interdisciplinary Science and Technology, Tarbiat Modares University, Tehran, Iran, Tehran, Iran
- 4 Tarbiat Modares University, Tehran, Iran
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.
Keywords: synNotch receptor, CAR-T cell therapy, Synthetic Biology, Immunotherapy, Cancer, Molecular logic-gates
Received: 14 Dec 2024; Accepted: 28 Mar 2025.
Copyright: © 2025 Shirzadian, Moori, Rabbani and Rahbarizadeh. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Fatemeh Rahbarizadeh, Tarbiat Modares University, Tehran, Iran
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