Treatment paradigms for B-cell lymphomas have evolved significantly in the last decades. Nevertheless, the widespread clinical use of immunotherapy has demonstrated that it invariably leads to the development of resistance. This review outlines the underlying molecular mechanisms of resistance associated with emerging immunotherapeutic strategies, including Chimeric Antigen Receptor (CAR) T cell therapy and bispecific antibodies (BsAbs). In high-grade B-cell lymphomas, nearly 50% of patients progress following CAR T treatment due to host-related factors affecting CAR T cell proliferation and persistence, as well as tumor-intrinsic factors, such as loss of CD19 epitope expression, trogocytosis, and other genomic alterations (e.g.,CD19mutations, chromothripsis, APOBEC mutational activity, and deletions ofRHOA). Additional genomic and epigenetic events, including mutations, alternative splicing ofCD19, and aberrant promoter methylation, further contribute to resistance. BsAbs, representing an off-the-shelf T-cell-redirecting strategy, have recently shown promising single-agent efficacy with a manageable toxicity profile, predominantly characterized by T cell overactivation syndromes. Similarly to CAR T cell therapy, BsAb resistance arises through diverse mechanisms, such as antigen loss, T cell dysfunction (exhaustion and regulatory T cell activation), tumor-intrinsic alterations (e.g.,TP53mutations andMYCamplifications), and immunosuppressive influences from the tumor microenvironment. These findings underscore the complexity of immune evasion in B-cell lymphomas and highlight the ongoing need to optimize immunotherapeutic strategies and develop combination approaches to overcome resistance.
在过去的几十年里，B细胞淋巴瘤的治疗模式已发生显著演变。然而，免疫疗法的广泛应用表明，其不可避免地会导致耐药性的产生。本综述概述了与新兴免疫治疗策略相关的耐药性分子机制，包括嵌合抗原受体（CAR）T细胞疗法和双特异性抗体（BsAbs）。在高级别B细胞淋巴瘤中，近50%的患者在接受CAR T治疗后出现疾病进展，这既与宿主相关因素（如影响CAR T细胞增殖和持久性的因素）有关，也与肿瘤内在因素相关，例如CD19表位表达缺失、胞啃作用及其他基因组改变（如CD19突变、染色体碎裂、APOBEC突变活性及RHOA缺失）。其他基因组和表观遗传事件，包括突变、CD19的可变剪接以及启动子异常甲基化，也进一步促进了耐药性的形成。BsAbs作为一种现成的T细胞重定向策略，近期已显示出良好的单药疗效及可控的毒性特征，主要表现为T细胞过度活化综合征。与CAR T细胞疗法类似，BsAb耐药性通过多种机制产生，例如抗原丢失、T细胞功能障碍（耗竭和调节性T细胞活化）、肿瘤内在改变（如TP53突变和MYC扩增）以及肿瘤微环境的免疫抑制影响。这些发现强调了B细胞淋巴瘤免疫逃逸机制的复杂性，并凸显了持续优化免疫治疗策略、开发联合方案以克服耐药性的迫切需求。
肿瘤(癌症)患者之家