肿瘤细胞治疗研究
英文原题：Novel therapeutic strategies targeting resistance mechanisms in hematologic malignancies: from BCL2 inhibition to immunomodulatory approaches.
这些策略代表着向精准医学的范式转变，但毒性以及生物标志物驱动的耐药等挑战依然存在。
**背景：**慢性淋巴细胞白血病（CLL）、急性髓系白血病（AML）、非霍奇金淋巴瘤（NHL）和多发性骨髓瘤（MM）等血液系统恶性肿瘤常因内在或获得性耐药而复发率较高。耐药机制通常涉及凋亡通路失调（例如B细胞淋巴瘤2家族蛋白BCL2过表达）及通过改变微环境发生免疫逃逸。 **目的：**本综述总结2020–2025年靶向这些机制的治疗策略进展，重点关注BCL2抑制和免疫调节方法，以克服耐药并改善结局。 **方法：**系统回顾PubMed、Nature及其他数据库中2020至2025年发表的临床试验、机制研究和新兴联合疗法。 **主要发现：**维奈克拉等BCL2抑制剂在CLL和AML中总体缓解率（ORR）已超过70%，但可因MCL1/BCL-XL上调而出现耐药；新一代药物（如sonrotoclax）及联合方案旨在解决这一问题。免疫调节酰亚胺类药物（IMiD）和CAR-T细胞免疫疗法等免疫调节策略可增强T/NK细胞活性，在复发MM中的客观缓解率最高可达90%。结合BCL2抑制与免疫疗法的整合策略显示协同效应，无进展生存期（PFS）提高30%–40%。 **结论：**这些策略代表向精准医疗转变，但毒性和生物标志物驱动的耐药等挑战仍然存在。未来方向包括AI指导的疗效预测及蛋白水解靶向嵌合体（PROTAC）等新型降解剂。
BACKGROUND: Hematologic malignancies, including chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM), are characterized by high relapse rates due to intrinsic and acquired drug resistance. Resistance mechanisms often involve dysregulation of apoptosis pathways, such as B-cell lymphoma 2 (BCL2) family overexpression, and immune evasion through microenvironment modulation. PURPOSE: This review synthesizes recent advances (2020-2025) in therapeutic strategies targeting these mechanisms, focusing on BCL2 inhibition and immunomodulatory approaches to overcome resistance and improve outcomes. METHODS: We systematically reviewed literature from PubMed, Nature, and other databases, emphasizing clinical trials, mechanistic studies, and emerging combinations published between 2020 and 2025. Main Findings: BCL2 inhibitors like venetoclax have achieved high response rates (ORR >70%) in CLL and AML but face resistance via MCL1/BCL-XL upregulation. Next-generation agents (e.g., sonrotoclax) and combinations address this. Immunomodulatory therapies, including immunomodulatory imide drugs (IMiDs) and chimeric antigen receptor T-Cell immunotherapy (CAR-T cells), enhance T/NK cell activity, with objective response rate (ORR) up to 90% in relapsed MM. Integrated strategies combining BCL2 inhibition with immunotherapy show synergistic effects, improving progression-free survival (PFS) by 30%-40%. CONCLUSION: These strategies represent a paradigm shift toward precision medicine, but challenges like toxicity and biomarker-driven resistance persist. Future directions include AI-guided predictions and novel degraders like proteolysis-targeting chimeras (PROTACs).
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