The molecules with double-edged sword roles in T cell: An implication for adoptive T cell therapy

Immune checkpoints have traditionally been viewed as inhibitory molecules that downregulate immune cell activity, acting as a safeguard against excessive immune responses. In chronic infections and cancer, however, these checkpoints serve as barriers that can inhibit effective immune responses, thereby reducing pathological consequences. Over the years, researchers have explored immune checkpoint blockade through antibody-based therapies and have sought to delete these molecules in adoptive T cell therapy to enhance T cell function and proliferation. However, emerging research suggests that immune checkpoint deletion may not always be advantageous; these molecules appear to play complex roles in supporting T cell functions like metabolism, cytotoxicity, proliferation and persistence. Some of them might have roles in T cell differentiation into subsets like memory cells. This article delves into the evolving understanding of immune checkpoint molecules, such as PD-1, TIM-2, A2aR, 2B4 and EP2, highlighting their nuanced roles in immune regulation and implications for immunotherapy. We proposed that these molecules should be viewed as a double-edged sword and regulated with greater caution, taking into account their lesser-known roles and other interacting factors.