Rewriting History: Epigenetic Reprogramming of CD8⁺ T Cell Differentiation to Enhance Immunotherapy

The full potential of T cell-based immunotherapies remains limited by a variety of T cell extrinsic and intrinsic immunosuppressive mechanisms that can become imprinted to stably reduce the antitumor ability of T cells. Here, we discuss recent insights into memory CD8⁺ T cell differentiation and exhaustion and the association of these differentiation states with clinical outcomes during immune checkpoint blockade and chimeric antigen receptor (CAR) T cell therapeutic modalities. We consider the barriers limiting immunotherapy with a focus on epigenetic regulation impeding efficacy of adoptively transferred T cells and other approaches that augment T cell responses such as immune checkpoint blockade. Furthermore, we outline conceptual and technical breakthroughs that can be applied to existing therapeutic approaches and to the development of novel cutting-edge strategies.