Epigenetic insights and innovations for overcoming barriers in CAR-T cell therapy for cancer

Over the past several decades, chimeric antigen receptor (CAR)-T cell therapy has revolutionized cancer immunotherapy, particularly for hematological cancers. However, its effectiveness against solid tumors is often hindered by numerous barriers. Advances in modern epigenomic profiling technologies have deepened our understanding of how epigenetic regulation shapes CAR-T cell behavior. Epigenetic mechanisms act as an unseen force that governs CAR-T cell fate by modulating key genes involved in metabolism, differentiation, phenotype, migration, persistence, and overall function. Recent innovations in epigenetic monitoring and manipulation have provided new strategies to address the challenges that restrict CAR-T cell performance. In this review, we examine the epigenetic landscape of CAR-T cells and discuss potential epigenetic-based strategies to enhance CAR-T cell function and overcome limitations in CAR-T cell therapy. Trial registration number: not applicable.