以 CD19 靶点为代表的嵌合抗原受体基因修饰 T（CAR-T）细胞在 B 细胞恶性肿瘤治疗中取得突破性进展，但随着 CAR-T细胞治疗患者数量的增加，复发、抵抗问题已成为临床亟待解决的问题和领域内研究热点。近年来除抗原丢失引发的免 疫逃逸及CAR-T细胞失能导致的治疗不敏感外，对于肿瘤细胞自身内在因素异常等导致的治疗抵抗的研究也取得了一定的进 展。基于高通量的筛选体系，促凋亡分子[如佛波醇-12-肉豆蔻酸-13-乙酸酯诱导蛋白-1（PMAIP1，又称NOXA）、Fas相关死亡域 蛋白（FADD）等]和黏附分子[如CD58、细胞间黏附分子-1（ICAM-1）等]表达降低或缺失介导的抵抗机制相继被识别。对于目前 已被识别的抵抗机制，已形成多种针对性的逆转策略，如组蛋白去乙酰化酶（HDAC）抑制剂联合CAR-T细胞治疗NOXA低表达 的非霍奇金淋巴瘤；表观遗传学药物预处理CAR-T细胞增加其抗瘤效能与持久性；通过基因编辑技术解除相关基因的抑制作用 从而增效CAR-T细胞；过表达细胞因子改善肿瘤微环境等，且部分策略已获得临床验证。本文综述已有CAR-T细胞治疗的抵抗 机制及其针对性逆转策略，分析了相关研究的临床转归，旨在为提升CAR-T细胞在B细胞肿瘤中的疗效提供新的思路。

Chimeric antigen receptor gene-modified T-cell (CAR-T cell), represented by the target CD19, has achieved breakthrough progress in the treatment of B-cell malignancies. However, with the increasing number of patients undergoing CAR-T cell therapy, the issue of relapse and resistance has become particularly prominent and is now a major clinical challenge and a research hotspot in the field. In recent years, in addition to immune escape due to antigen loss and treatment insensitivity caused by CAR-T cells dysfunction, progress has been made in understanding resistance mechanisms caused by intrinsic factors of tumor cells. Using high throughput screening system, resistance mechanisms mediated by downregulation or deficient expression of pro-apoptotic molecules (such as NOXA, FADD) and adhesion molecules (such as CD58, ICAM1) have been identified. Several strategies have been developed to reverse these resistance mechanisms, such as HDAC inhibitors combined with CAR-T cell therapy to treat NOXA-low expressing nonHodgkin lymphoma; pretreatment of CAR-T cells with epigenetic drugs to enhance their antitumor efficacy and persistence; using gene editing technologies to relieve gene suppression and enhance CAR-T cell activity; and overexpressing cytokines to improve tumor microenvironment. Some of these strategies have already been clinically validated. This review aims to summarize the existing resistance mechanisms to CAR-T cell therapy and their targeted reversal strategies, analyze the clinical outcomes of related studies, and provide new insights into enhancing CAR-T cell efficacy in B-cell malignancies.

国家自然科学基金重点项目（No. 82430012）；国家自然科学基金面上项目（No. 82370226）；北京市自然科学基金项目（No.7232160）； 国家自然科学基金青年项目（No.82400265）