肿瘤细胞治疗研究
英文原题：Decoding immunotherapy resistance in multiple myeloma: genetic insights and approaches to counter resistance.
多发性骨髓瘤（MM）是一种以浆细胞克隆性增殖为特征的血液系统恶性肿瘤，因其固有的异质性以及频繁对免疫治疗产生耐药，带来重大的治疗挑战。
多发性骨髓瘤（MM）是一种以浆细胞克隆性增殖为特征的血液系统恶性肿瘤，其内在异质性以及对免疫治疗频繁产生耐药，使治疗面临重大挑战。近期免疫治疗策略取得进展，包括免疫调节药物（IMiD）、CAR-T 细胞疗法、单克隆抗体（mAb）、抗体药物偶联物（ADC）和双特异性抗体（BsAb），显著改善了患者结局，但疾病复发几乎不可避免。本综述系统归纳 MM 免疫治疗耐药机制，考察肿瘤细胞内在因素（包括遗传和表观遗传改变、靶抗原调节或丢失）、免疫效应细胞功能障碍（如 T 细胞耗竭）以及骨髓微环境复杂的免疫抑制特征。此外，文章讨论单细胞测序、基于 CRISPR/Cas9 的功能筛选等新兴技术如何揭示耐药通路并指导靶点发现。最后，综述重点介绍克服耐药的合理策略，包括协同联合方案、开发下一代疗法，以及重编程肿瘤微环境的方法。这些见解为设计更有效、疗效更持久的 MM 免疫治疗提供了概念框架。
Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of plasma cells and presents major therapeutic challenges due to its intrinsic heterogeneity and frequent development of resistance to immunotherapy. Although recent advances in immunotherapeutic strategies, including immunomodulatory drugs (IMiDs), chimeric antigen receptor T-cell (CAR-T) therapies, monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), and bispecific antibodies (BsAbs), have significantly improved patient outcomes, disease relapse remains nearly inevitable. This review systematically categorizes resistance mechanisms to immunotherapy in MM by examining intrinsic tumor cell factors, including genetic and epigenetic alterations, modulation or loss of target antigens, immune effector cell dysfunction such as T-cell exhaustion, and the complex suppressive features of the bone marrow microenvironment. In addition, we discuss the application of emerging technologies such as single-cell sequencing and CRISPR/Cas9-based functional screening to uncover resistance pathways and guide target discovery. Finally, we highlight rational strategies to overcome resistance, including synergistic combination regimens, development of next-generation therapeutics, and approaches to reprogram the tumor microenvironment. These insights provide a conceptual framework for the design of more effective and durable immunotherapeutic interventions in MM.
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