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

SIMPLE SUMMARY: Epigenetic mechanisms are key players in many diseases, including cancer. Unlike genetic changes, epigenetic modifications are reversible without leaving a permanent mark on DNA. Epigenetic therapies, using epigenome-influencing techniques, aim to normalize DNA methylation patterns or post-translational modifications on histones, ultimately reversing a malignant phenotype. Chimeric antigen receptor T cells (CAR-Ts) have revolutionized our therapeutic approach to cancer; however, several challenges need to be overcome that are currently limiting a broader application of CAR-T cell therapy. Epigenetic remodeling of CAR-T cells may unleash their potential by diminishing exhaustion, improving trafficking and penetrating capacity, and promoting the memory phenotype, ultimately resulting in increased CAR-T cell persistence and improved outcomes. ABSTRACT: 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.