Zheng Yue, Zhu Qiuyi, Li Xiaoran, Ge Tongxin, Wang Shaoyun, Jia Renbing, Yang Ludi, Wang Yefei, Zhuang Ai
State Key Laboratory of Eye Health, Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China.
State Key Laboratory of Eye Health, Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China.
Biotechnol Adv. 2025 Oct;83:108649. doi: 10.1016/j.biotechadv.2025.108649. Epub 2025 Jul 19.
Chimeric antigen receptor (CAR) T cell therapy has emerged as a pivotal treatment modality for advanced hematological malignancies. However, clinical evidence suggests that CAR T cell therapy has a low response rate, poor efficacy for solid tumor, and a high complication rate. Recent research highlighted the crucial role of epigenetics in tumor immunity, particularly in modulating the fate and function of T cells. The epigenetic landscapes among T cell subpopulations show substantial differences, which in turn have a profound impact on the effector function and persistence of T cells. Epigenetic reprogramming holds promise for enhancing the persistence of CAR T cells, augmenting T cell infiltration, and ameliorating the immunosuppressive microenvironment while impeding immune evasion. In addition, biomarkers derived from the epigenetics serve as indicators to predict patient prognosis. In recent years, a growing number of clinical trials have been initiated to explore the combination of epigenetic drugs with CAR T cell therapy, highlighting the therapeutic promise of this synergistic approach in improving efficacy and overcome therapeutic resistance. However, the non-specificity of epigenetic drugs, side effects of epigenetic gene editing, poor efficacy in solid tumors, and instability of epigenetic biomarkers for predicting prognosis remain areas for further exploration. In this review, we explored the characterization of epigenetic modification landscapes across CAR T cell subpopulations, discussed how epigenetic reprogramming addresses challenges associated with CAR T cell therapy, and provided insights into the limitations of combining epigenetic strategies with CAR T cell therapy.
嵌合抗原受体（CAR）T细胞疗法已成为晚期血液系统恶性肿瘤的关键治疗方式。然而，临床证据表明，CAR T细胞疗法的缓解率较低，对实体瘤疗效不佳，且并发症发生率较高。近期研究突出了表观遗传学在肿瘤免疫中的关键作用，尤其是在调节T细胞的命运和功能方面。T细胞亚群之间的表观遗传格局存在显著差异，这反过来又对T细胞的效应功能和持久性产生深远影响。表观遗传重编程有望增强CAR T细胞的持久性，增加T细胞浸润，改善免疫抑制微环境，同时阻碍免疫逃逸。此外，源自表观遗传学的生物标志物可作为预测患者预后的指标。近年来，越来越多的临床试验已启动，以探索表观遗传药物与CAR T细胞疗法的联合应用，凸显了这种协同方法在提高疗效和克服治疗耐药性方面的治疗前景。然而，表观遗传药物的非特异性、表观遗传基因编辑的副作用、在实体瘤中的疗效不佳以及用于预测预后的表观遗传生物标志物的不稳定性，仍是有待进一步探索的领域。在本综述中，我们探讨了CAR T细胞亚群表观遗传修饰格局的特征，讨论了表观遗传重编程如何应对与CAR T细胞疗法相关的挑战，并深入分析了将表观遗传策略与CAR T细胞疗法相结合的局限性。
