靶向 CD19 (CAR-19) 的嵌合抗原受体 T 细胞疗法可促进历史上预后不良的复发或难治性 (rel/ref) 大 B 细胞淋巴瘤 (LBCL) 患者获得令人印象深刻的持久缓解。尽管如此，超过一半的患者仍然无法做出反应或最终取得进展。揭示耐药机制的研究检查了宿主临床参数、CAR-19产品成分和肿瘤微环境（TME）的改变，而分析肿瘤细胞基因组改变的贡献的研究相对较少。与结果相关的因素包括肿瘤体积增加、输注 CAR-T 产品的具体特征、肿瘤微环境中骨髓细胞的浸润以及 LBCL 基因组复杂性标记。目前的文献中基本上没有针对耐药性的功能性实验室研究，这说明需要在遗传精确的免疫活性系统中进行实验，以确认候选改变在耐药性中的作用并为未来的改进提供信息。在这篇综述中，我们重点介绍了阐明宿主耐药性生物标志物、CAR 产品、TME 以及相对而言研究不足的肿瘤基因组编码的肿瘤内在介质的关键研究。我们得出了一个适合 CAR-19 抗性生物标志物识别和实验室功能验证的实验框架。

Chimeric antigen receptor T-cell therapy targeting CD19 (CAR-19) promotes impressive durable remissions for relapsed or refractory (rel/ref) large B-cell lymphoma (LBCL) patients with historically poor prognoses. Despite this, over half of patients still fail to respond or eventually progress. Studies to reveal mechanisms of resistance have examined host clinical parameters, CAR-19 product composition, and tumor microenvironment (TME) alterations, while a relative paucity of studies has analyzed contributions by genomic alterations in tumor cells. Factors associated with outcome include increased tumor volume, specific characteristics of infused CAR-T products, infiltration by myeloid cells in tumor microenvironments, and markers of complexity in LBCL genomes. Functional laboratory studies of resistance are largely absent in the current literature, illustrating a need for experiments in genetically accurate immunocompetent systems to confirm candidate alterations' roles in resistance and inform future improvements. In this review, we highlight key studies that have elucidated biomarkers of resistance in hosts, CAR products, TMEs, and comparatively understudied tumor-intrinsic mediators encoded by tumor genomes. We conclude with an experimental framework suitable for CAR-19 resistance biomarker identification and laboratory functional validation.