iPSC-Derived T and CAR-T Cells of Distinct Phenotypes: Current Protocols, Challenges and Potential for Cancer Treatment

Adoptive T-cell therapy has demonstrated substantial clinical efficacy in several hematological malignancies, but autologous manufacturing remains limited by variability in starting cell material, manufacturing time, product heterogeneity, and T-cell dysfunction. Induced pluripotent stem cells (iPSCs) provide a potentially scalable and genetically engineerable source for the generation of standardized allogeneic T-cell products. This review summarizes current approaches to the differentiation of iPSCs into distinct T-cell phenotypes and evaluates their potential for cancer immunotherapy. We first discuss iPSC-derived conventional αβ T cells, including recent advances in feeder-free and scalable differentiation, maturation, and genetic engineering, as well as preclinical and early clinical evidence. We then examine γδ T cells, invariant natural killer T cells, and mucosal-associated invariant T cells, focusing on their distinctive antigen-recognition mechanisms, effector functions, tissue tropism, differentiation strategies, and therapeutic applications. Across these populations, iPSC technology may facilitate standardized and scalable production while enabling targeted engineering of T-cell specificity and functional properties. However, important challenges remain, including efficient lineage-specific differentiation, maturation, phenotypic consistency, long-term persistence, tumor infiltration, and control of alloreactivity and immunogenicity. Overall, iPSC-derived T cells represent a versatile platform for developing diverse cellular immunotherapies, although their clinical potential remains dependent on further technological and translational advances.