Advancing adoptive cellular immunotherapy via Notch-based ex vivo T cell development platforms

T cell-based immunotherapies represent one of the most promising areas in cancer treatment, offering the dual advantages of precise molecular targeting and durable therapeutic effects. Notch signaling platforms facilitate the ex vivo generation of T lineage cells from hematopoietic stem and progenitor cells sourced from bone marrow, peripheral blood, cord blood, or pluripotent stem cells. These platforms can be tailored to produce either T cell progenitors or fully differentiated T cells. The use of T cell precursors in adoptive cell therapy enables off-the-shelf immunotherapy, as even fully HLA-mismatched allogeneic T cell precursors undergo thymic selection and are tolerized during maturation in the recipient's thymus. Furthermore, T lineage cells produced via Notch-based systems can be engineered to express chimeric antigen receptors, resulting in potent, tumor-specific therapeutic products. Notch-based in vitro T cell development platforms range from stromal cell-dependent co-cultures to clinically suitable, stromal cell-free systems using immobilized Notch ligands, ligand-coated microbeads or soluble Notch agonists. Enhancements such as incorporating VCAM-1 alongside Notch signaling have been introduced to improve the efficiency of T cell production. This review highlights the various Notch signaling platforms that have contributed - and continue to contribute - to the advancement of adoptive T cell immunotherapy.