CAR-engineered neutrophils derived from induced pluripotent stem cells: a new frontier in cellular immunotherapy

Adoptive cell therapy has been revolutionized by chimeric antigen receptor (CAR)-based immunotherapy, but its applications are still mainly limited to T and natural killer (NK) cells. The FDA-approved seven CAR-T products in less than ten years, demonstrating the high capacity of this approach. However, given the limitations of CAR-T cell therapy, such as low tumor infiltration and clinical efficacy in solid tumors, there has been significant interest in recent years to engineer other immune cell types, including neutrophils, with CARs because they provide special advantages for cancer therapy, such as rapid infiltration into tumor sites, strong cytotoxic functions, and the ability to modify the tumor microenvironment (TME). However, the main barriers to the practical translation of CAR-neutrophils are their short lifespan, restricted ex vivo proliferation, and inherent resistance to genetic alterations, which calls for the availability of an infinite source for the ongoing supply of CAR-neutrophil therapy. These obstacles may be overcome by developments in induced pluripotent stem cell (iPSC) technology, which offers a consistent, renewable, and genetically changeable source of CAR-neutrophils (CAR-Neuts). The goal of this study is to present a comprehensive analysis of the state, gaps, and potential future directions of this recently developed topic.