Engineering resilient CAR T cells for immunosuppressive environment

Chimeric antigen receptor (CAR) T cell therapy has revolutionized cancer treatment and is now being explored for other diseases, such as autoimmune disorders. While the tumor microenvironment (TME) in cancer is often immunosuppressive, in autoimmune diseases, the environment is typically inflammatory. Both environments can negatively impact CAR T cell survival: the former through direct suppression, hypoxia, and nutrient deprivation, and the latter through chronic T cell receptor (TCR) engagement, risking exhaustion. Mechanisms of resistance include T cell exhaustion, dysfunction, and the impact of the TME. Chronic antigenic stimulation leads to CAR T cell exhaustion. CAR construct design, including co-stimulatory domains, hinge, transmembrane regions, promoters, the affinity of the binder site, and on/off rate plays a crucial role in modulating CAR T cell function and resistance. This review discusses the impact of the in vitro development of CAR T cells, albeit in relation to the TME, on therapeutic outcomes. The use of alternative cell sources, multi-antigen targeting, and reengineering the TME, are discussed. The review emphasizes the need for continued innovation in CAR T cell design and manufacturing to optimize therapeutic efficacy and durability, especially in the face of varying environmental challenges.