Epigenetic landscapes drive CAR-T cell kinetics and fate decisions: Bridging persistence and resistance

Chimeric antigen receptor-T (CAR-T) cell therapy has revolutionized the treatment paradigm for B-cell malignancies and holds promise for solid tumor immunotherapy. However, CAR-T-cell therapy still faces many challenges, especially primary and secondary resistance. Some mechanisms of resistance, including CAR-T-cell dysfunction, an inhibitory tumor microenvironment, and tumor-intrinsic resistance, have been identified in previous studies. As insights into CAR-T-cell biology have increased, the role of epigenetic reprogramming in influencing the clinical effectiveness of CAR-T cells has become increasingly recognized. An increasing number of direct and indirect epigenetic targeting methods are being developed in combination with CAR-T-cell therapy. In this review, we emphasize the broad pharmacological links between epigenetic therapies and CAR-T-cell therapy, not only within CAR-T cells but also involving tumors and the tumor microenvironment. To elucidate the mechanisms through which epigenetic therapies promote CAR-T-cell therapy, we provide a comprehensive overview of the epigenetic basis of CAR-T-cell kinetics and differentiation, tumor-intrinsic factors and the microenvironment. We also describe some epigenetic strategies that have implications for CAR-T-cell therapy in the present and future. Because targeting epigenetics can have pleiotropic effects, developing more selective and less toxic targeting strategies and determining the optimal administration strategy in clinical trials are the focus of the next phase of research. In summary, we highlight the possible mechanisms and clinical potential of epigenetic regulation in CAR-T-cell therapy.