Engineering strategies and therapeutic applications of synthetic Notch (synNotch) receptors in cancer therapeutics

• The review covers synthetic Notch (synNotch) receptors, modular synthetic receptors that enable customizable, antigen-specific activation of immune cells for precision cancer therapy. • The logic-gated synNotch–chimeric antigen receptor (CAR) systems enhance tumour targeting while minimizing off-tumour toxicity, especially in CAR-T cell engineering. • Added preclinical data suggest synNotch as a future-ready cancer therapy tool. • The present review addresses the challenges, including immunogenicity, off-target effects, and delivery, and how to overcome them by advanced engineering strategies. Synthetic Notch (synNotch) receptors have been developed as a novel approach to cell-based immunotherapy and will provide programmable, specific cancer treatments. Unlike existing fixed chimeric antigen receptor (CAR)-T cell therapies, synNotch receptors are a combination of modular domains, such as extracellular, transmembrane, and intracellular domains, for influencing gene expression depending on the present ligand. Through Boolean logic-based cellular decisions, synNotch receptors allow for a higher degree of precision and a lower degree of off-target effects. Logic-regulated circuits use pairs of ligands and receptors to detect indicators of the tumour microenvironment in a highly specific manner. The potential of synNotch in solid tumours such as glioma and pancreatic cancer has been demonstrated in preclinical models using CAR expression control and the ability to regulate cytokines, a method that could break through the obstacles of immunosuppressive niches and antigen escape. Continuous developments are resolving engineering challenges, and the fusion of synNotch with technologies such as CAR-T or induced pluripotent stem cells could be a transformative approach in cancer therapy.