肿瘤细胞治疗研究
英文原题：Breaking the relapse barrier: innovative approaches to improve CAR T-cell efficacy by targeting leukemic stem cells (LSCs) and measurable residual disease (MRD) in acute myeloid leukemia.
Breaking the relapse barrier: innovative approaches to improve CAR T-cell efficacy by targeting leukemic stem cells (LSCs) and measurable residual disease (MRD) in acute myeloid leukemia.
急性髓系白血病（AML）具有生物学异质性、临床侵袭性，其特征为未成熟髓系祖细胞在骨髓微环境中不受控制的克隆性扩增。
急性髓系白血病 (AML) 具有生物学异质性、临床侵袭性，其特征是未成熟髓系祖细胞在骨髓微环境中不受控制地克隆性扩增。尽管一线治疗可获得缓解，但复发极为常见，并且是治疗失败和患者死亡的主要决定因素。这种复发的背后是白血病干细胞 (LSCs) 与可测量残留病 (MRD) 细胞之间隐匿的协同关系，这些细胞稀少、治疗难治，深居于骨髓龛中，并受到支持免疫逃逸和存活的细胞及分子信号保护。这些恶性储库是沉默的复发构建者，即使在临床上无病的患者中也会引发疾病复发。细胞免疫治疗的进展揭示了 CAR T 细胞作为精准制导子弹突破这一庇护所的前景。通过对 CAR T 细胞进行特异性改造，使其特异性识别并靶向 LSCs 和 MRD，现在有可能靶向 AML 持续存在的真正原因。本综述批判性地评述了复发起始细胞的分子特征和保护机制，并介绍了创新性 CAR T 细胞工程策略，尤其是缺氧响应型、多靶点、逻辑门控和装甲 CAR 方法，这些策略旨在破坏骨髓龛、消除恶性干性、克服工程化 T 细胞耗竭，并重新定义 AML 的治疗前景。
Acute Myeloid Leukemia (AML) is biologically heterogeneous, clinically aggressive and is characterized by the uncontrolled clonal expansion of immature myeloid progenitors in the bone marrow microenvironment. Despite the achievement of remission with frontline treatments, relapse is disturbingly common and is the major determinant of therapeutic failure and patient mortality. Underlying this recurrence is the insidious partnership between leukemic stem cells (LSCs) and measurable residual disease (MRD) cells, which are rare, therapy-refractory cells that reside deep in the bone marrow niche and are protected by cellular and molecular signals that support immune evasion and survival. These malignant reservoirs are the silent relapse architects that launch disease recurrence even in clinically disease-free patients. Advances in cellular immunotherapy have revealed the promise of Chimeric Antigen Receptor (CAR) T cells as precision-guided bullets that break through this sanctuary. With the specific modification of CAR T cells to specifically recognize and target LSCs and MRD, it is now possible to target the real cause of AML persistence. This review critically reviews the molecular signatures and protective mechanisms of relapse-initiating cells and introduces innovative CAR T cell engineering strategies, especially hypoxia-responsive, multi-target, logic-gated, and armored CAR approaches that are aimed at disrupting the bone marrow niche, eliminating malignant stemness, overcoming exhaustion of engineered T cells and redefining the therapeutic horizon of AML.
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