Wang Kecheng, Ou Kaixin, Zeng Yifei, Yue Chunyan, Zhuo Yaqi, Wang Langqi, Chen Huifang, Tu Sanfang
Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, China; The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510280, China.
Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, China.
Crit Rev Oncol Hematol. 2025 Jul;211:104729. doi: 10.1016/j.critrevonc.2025.104729. Epub 2025 Apr 15.
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.
嵌合抗原受体T细胞（CAR-T）疗法彻底改变了B细胞恶性肿瘤的治疗模式，并为实体瘤免疫治疗带来了希望。然而，CAR-T细胞疗法仍面临许多挑战，尤其是原发性和继发性耐药。先前的研究已经确定了一些耐药机制，包括CAR-T细胞功能障碍、抑制性肿瘤微环境和肿瘤内在耐药。随着对CAR-T细胞生物学认识的增加，表观遗传重编程在影响CAR-T细胞临床疗效中的作用越来越受到认可。越来越多的直接和间接表观遗传靶向方法正在与CAR-T细胞疗法联合开发。在本综述中，我们强调表观遗传疗法与CAR-T细胞疗法之间广泛的药理学联系，不仅涉及CAR-T细胞内部，还涉及肿瘤和肿瘤微环境。为了阐明表观遗传疗法促进CAR-T细胞疗法的机制，我们全面概述了CAR-T细胞动力学和分化的表观遗传基础、肿瘤内在因素和微环境。我们还描述了一些对当前和未来CAR-T细胞疗法有影响的表观遗传策略。由于靶向表观遗传可能具有多效性，因此开发更具选择性和更低毒性的靶向策略以及确定临床试验中的最佳给药策略是下一阶段研究的重点。总之，我们强调了表观遗传调控在CAR-T细胞疗法中的可能机制和临床潜力。
