[Strategies to overcome CAR-T cell exhaustion and terminal differentiation]

Adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells has been successfully established in B-cell malignancies and multiple myeloma. The fitness of infused CAR-T cells is closely associated with durable clinical responses. Terminal differentiation, which compromises long-term persistence, and exhaustion, which dampens effector function, are major drivers of T-cell dysfunction. Recent studies have demonstrated that genetic engineering approaches that modulate gene expression and epigenetic programs can counteract these mechanisms and enhance T-cell function. In addition, strategies to augment T-cell function through artificial cytokine signaling have been extensively investigated. This review discusses these recent advancements.