Empowering the Potential of CAR-T Cell Immunotherapies by Epigenetic Reprogramming

T-cell-based, personalized immunotherapy can nowadays be considered the mainstream treatment for certain blood cancers, with a high potential for expanding indications. Chimeric antigen receptor T cells (CAR-Ts), an ex vivo genetically modified T-cell therapy product redirected to target an antigen of interest, have achieved unforeseen successes in patients with B-cell hematologic malignancies. Frequently, however, CAR-T cell therapies fail to provide durable responses while they have met with only limited success in treating solid cancers because unique, unaddressed challenges, including poor persistence, impaired trafficking to the tumor, and site penetration through a hostile microenvironment, impede their efficacy. Increasing evidence suggests that CAR-Ts' in vivo performance is associated with T-cell intrinsic features that may be epigenetically altered or dysregulated. In this review, we focus on the impact of epigenetic regulation on T-cell differentiation, exhaustion, and tumor infiltration and discuss how epigenetic reprogramming may enhance CAR-Ts' memory phenotype, trafficking, and fitness, contributing to the development of a new generation of potent CAR-T immunotherapies.

Automated summary

T-cell-based, personalized immunotherapy has become the mainstream treatment for certain blood cancers and shows potential for further indications. However, CAR-T cell therapies, which are genetically modified T-cell therapies targeting specific antigens, face challenges in providing durable responses and achieving success in treating solid cancers. These challenges include poor persistence, impaired tumor trafficking, and difficulties in penetrating the hostile tumor microenvironment. Increasing evidence suggests that epigenetic regulation plays a role in the in vivo performance of CAR-T cells. Understanding the impact of epigenetic reprogramming on T-cell differentiation, exhaustion, and tumor infiltration may lead to the development of more potent CAR-T immunotherapies.