Macrophages as Potential Therapeutic Targets in Acute Myeloid Leukemia 作为急性髓性白血病潜在治疗靶点的巨噬细胞
Oana Serban ^(5){ }^{5}, Mihnea Zdrenghea ^(1,2,**){ }^{1,2, *} ( and Ana Maria Nanut Oana Serban , Mihnea Zdrenghea ( 和 Ana Maria Nanut)^(6){ }^{6}
1 Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes Str., 400012 Cluj-Napoca, Romania 1 血液学系，Iuliu Hatieganu 医药大学，地址：8 Babes Str.
2 Department of Hematology, Ion Chiricuta Oncology Institute, 34-36 Republicii Str., 400015 Cluj-Napoca, Romania 2 罗马尼亚克卢日-纳波卡共和国大街 34-36 号 Ion Chiricuta 肿瘤研究所血液科，邮编 400015
3 Department of Pathology, Ion Chiricuta Oncology Institute, 34-36 Republicii Str., 400015 Cluj-Napoca, Romania 3 病理学系，Ion Chiricuta 肿瘤研究所，地址：34-36 Republicii Str.
4 Octavian Fodor" Regional Institute of Gastroenterology and Hepatology, 19-21 Croitorilor Str., 400162 Cluj-Napoca, Romania 4 Octavian Fodor" 地区肠胃病学和肝病学研究所，地址：19-21 Croitorilor Str.
5 Regina Maria" Regional Laboratory in Cluj-Napoca, 109 Observatorului Str., 400363 Cluj-Napoca, Romania 5 Regina Maria "克卢日-纳波卡地区实验室，109 Observatorului Str.，400363 Cluj-Napoca，Romania
6 Regina Maria" Regional Laboratory in Cluj-Napoca, 34-36 Republicii Str., 400015 Cluj-Napoca, Romania 6 Regina Maria" Regional Laboratory in Cluj-Napoca, 34-36 Republicii Str.
Acute myeloid leukemia (AML) is a heterogenous malignant hemopathy, and although new drugs have emerged recently, current treatment options still show limited efficacy. Therapy resistance remains a major concern due to its contribution to treatment failure, disease relapse, and increased mortality among patients. The underlying mechanisms of resistance to therapy are not fully understood, and it is crucial to address this challenge to improve therapy. Macrophages are immune cells found within the bone marrow microenvironment (BMME), of critical importance for leukemia development and progression. One defining feature of macrophages is their plasticity, which allows them to adapt to the variations in the microenvironment. While this adaptability is advantageous during wound healing, it can also be exploited in cancer scenarios. Thus, clinical and preclinical investigations that target macrophages as a therapeutic strategy appear promising. Existing research indicates that targeting macrophages could enhance the effectiveness of current AML treatments. This review addresses the importance of macrophages as therapeutic targets including relevant drugs investigated in clinical trials such as pexidartinib, magrolimab or bexmarilimab, but also provides new insights into lesser-known therapies, like macrophage receptor with a collagenous structure (MACRO) inhibitors and Toll-like receptor (TLR) agonists. 急性髓性白血病（AML）是一种异质性恶性血液病，虽然最近出现了一些新药，但目前的治疗方案仍显示出有限的疗效。由于耐药性会导致治疗失败、疾病复发和患者死亡率上升，因此耐药性仍是一个主要问题。耐药性的根本机制尚未完全明了，因此解决这一难题对改善治疗至关重要。巨噬细胞是存在于骨髓微环境（BMME）中的免疫细胞，对白血病的发生和发展至关重要。巨噬细胞的一个显著特点是其可塑性，这使它们能够适应微环境的变化。虽然这种适应性在伤口愈合过程中很有利，但在癌症情况下也可加以利用。因此，以巨噬细胞为靶点作为治疗策略的临床和临床前研究似乎大有可为。现有研究表明，以巨噬细胞为靶点可以提高目前急性髓细胞白血病治疗的效果。本综述论述了巨噬细胞作为治疗靶点的重要性，包括在临床试验中研究的相关药物，如哌西达替尼、麦格列单抗或贝沙利单抗，同时也对一些鲜为人知的疗法，如具有胶原结构的巨噬细胞受体（MACRO）抑制剂和Toll样受体（TLR）激动剂提供了新的见解。
Acute myeloid leukemia (AML) is a heterogeneous cancer marked by the rapid increase in clonal myeloid progenitors (blasts) in the bone marrow and/or peripheral blood. Currently, the AML curability rate does not exceed 50%50 \% even for patients younger than 60 years [1], who are typically able to withstand intensive treatment approaches. Macrophages are phagocytic cells that are vital for the physiological functioning of innate immunity. The various functions of macrophages are related to their plasticity, a feature that characterizes macrophages and allows them to adapt to the changes within the tumor microenvironment (TME). In response to TME stimuli, macrophages can polarize to different forms, notably M1 and M2 macrophages. In response to the action of extrinsic factors in the tissue microenvironment, macrophages initiate various intracellular pathways that trigger their development towards distinct phenotypes. Apart from their immune role, a certain 急性髓性白血病（AML）是一种异质性癌症，其特点是骨髓和/或外周血中的克隆性髓性祖细胞（血泡）迅速增加。目前，即使是年龄小于 60 岁的患者，AML 的治愈率也不超过 50%50 \% [1]，这些患者通常能够承受强化治疗方法。巨噬细胞是一种吞噬细胞，对先天性免疫的生理功能至关重要。巨噬细胞的各种功能与其可塑性有关，这是巨噬细胞的一个特征，使其能够适应肿瘤微环境（TME）的变化。在肿瘤微环境的刺激下，巨噬细胞可极化为不同的形态，特别是 M1 和 M2 巨噬细胞。在组织微环境中外在因素的作用下，巨噬细胞启动各种细胞内途径，促使其向不同的表型发展。除了免疫作用外，巨噬细胞还具有一定的
subtype of macrophages manifests a protective and nurturing effect, favoring neoplastic cells. These are called tumor-associated macrophages (TAMs) [2]. As a response to an unhealthy malignant microenvironment, TAMs become activated and switch to specific phenotypes, participating in and supporting tumor progression. They are found in the TME of various leukemia types, where they are referred to as leukemia-associated macrophages (LAMs) and are linked to disease progression [3]. 一种亚型巨噬细胞具有保护和培育作用，有利于肿瘤细胞。这些巨噬细胞被称为肿瘤相关巨噬细胞（TAMs）[2]。作为对不健康的恶性微环境的一种反应，TAMs 被激活并转换为特定的表型，参与并支持肿瘤的进展。它们存在于各种类型白血病的 TME 中，被称为白血病相关巨噬细胞（LAMs），并与疾病进展有关[3]。
LAMs reside within the bone marrow microenvironment (BMME), which is formed of different cell types, such as osteoclasts, stromal cells, vascular endothelial cells, and immune effectors like natural killer (NK) cells [4]. LAMs are crucial components of the TME and they influence tumor progression. They produce a range of cytokines, chemokines, and proteases that can facilitate immunosuppression and induce tumor growth and metastasis [5]. LAMs 存在于骨髓微环境（BMME）中，骨髓微环境由不同类型的细胞组成，如破骨细胞、基质细胞、血管内皮细胞和免疫效应细胞（如自然杀伤（NK）细胞）[4]。LAMs是TME的重要组成部分，它们会影响肿瘤的进展。它们产生一系列细胞因子、趋化因子和蛋白酶，可促进免疫抑制，诱导肿瘤生长和转移 [5]。
This work focuses on LAMs as targets for therapy, reviewing the most recent research and clinical trials. We will start by discussing the functions of macrophages, including the currently accepted paradigm of their polarization. Next, we will address the protumorigenic role of TAMs in neoplastic disease and focus on LAMs’ relevance in AML. The final section is dedicated to past and present attempts at using macrophages as therapeutic targets in AML. 这项工作的重点是将 LAMs 作为治疗目标，回顾最新的研究和临床试验。我们将首先讨论巨噬细胞的功能，包括目前公认的巨噬细胞极化范式。接下来，我们将讨论 TAMs 在肿瘤性疾病中的原发作用，并重点讨论 LAMs 在急性髓细胞性白血病中的相关性。最后一部分将专门介绍过去和现在将巨噬细胞作为急性髓细胞白血病治疗靶点的尝试。
2. The Functions of Macrophages 2.巨噬细胞的功能
In the 19th century, Ilya Metchnikoff was the first scientist who studied macrophages, and later, in 1960, Van Fürth noted that all macrophages originate from circulating blood monocytes [6-10]. However, recent findings revealed that his theory was only partially true, as some macrophages are present from embryogenesis and continue to exist in tissues, regardless of monocytes [11-17]. 19 世纪，伊利亚-梅奇尼科夫（Ilya Metchnikoff）是第一位研究巨噬细胞的科学家，后来在 1960 年，范-菲尔特（Van Fürth）指出，所有巨噬细胞都起源于循环血液中的单核细胞[6-10]。然而，最近的研究结果表明，他的理论只是部分正确，因为有些巨噬细胞从胚胎发育开始就存在，并继续存在于组织中，与单核细胞无关[11-17]。
Macrophages are phagocytic cells, involved in innate immunity. Additionally, they participate in adaptative immunity by initiating specific defense mechanisms and recruiting immune cells, including lymphocytes [18]. Macrophages are known as antigen-presenting cells (APCs) because they protect against pathogens by recognizing and phagocytizing non-self-organisms, delivering the antigens to adaptive immune cells. Once activated, macrophages secrete cytokines and chemokines that initiate the process known as inflammation and influence the microenvironment [19,20]. Inflammation is a physiological reaction to infections or injuries, including microbial attacks or trauma. It is essential for maintaining homeostasis and is a highly regulated process comprising pro-inflammatory and anti-inflammatory elements [21]. During the initial phases of inflammation, macrophages destroy abnormal cells and remove apoptotic bodies [22]. 巨噬细胞是吞噬细胞，参与先天性免疫。此外，它们还通过启动特定防御机制和招募免疫细胞（包括淋巴细胞）参与适应性免疫 [18]。巨噬细胞被称为抗原递呈细胞（APC），因为它们通过识别和吞噬非自身有机体来抵御病原体，并将抗原递呈给适应性免疫细胞。巨噬细胞一旦被激活，就会分泌细胞因子和趋化因子，启动炎症过程并影响微环境 [19,20]。炎症是对感染或损伤（包括微生物攻击或创伤）的一种生理反应。它对维持体内平衡至关重要，是一个由促炎和抗炎因素组成的高度调节过程[21]。在炎症的初始阶段，巨噬细胞会摧毁异常细胞并清除凋亡体[22]。
When macrophages engulf pathogens, they process the antigens and display them on the surface of their membrane. This allows B cells and T-helper cells to recognize these antigens, particularly those encoded by major histocompatibility complex II (MHC II). After antigen recognition, TT cells produce cytokines to stimulate BB cells, which will release antibodies specific to the antigen [23]. Macrophages have increased heterogeneity due to their diversity of surface receptors [24]. 当巨噬细胞吞噬病原体时，它们会处理抗原并将其显示在细胞膜表面。这样，B细胞和T辅助细胞就能识别这些抗原，特别是主要组织相容性复合体II（MHC II）编码的抗原。抗原识别后， TT 细胞会产生细胞因子，刺激 BB 细胞，后者会释放针对抗原的特异性抗体[23]。巨噬细胞因其表面受体的多样性而增加了异质性[24]。
Alongside neutrophils, macrophages serve as the primary defense mechanism against pathogen invasion. However, their phagocytic ability decreases with aging [25,26]. When macrophages are exposed to inflammatory stimuli, they secret cytokines such as tumor necrosis factor (TNF), inflammation-associated interleukins such as IL-1, IL-6, IL-8, and IL-12, chemokines, leukotrienes, and prostaglandins, which can enhance vascular permeability and attract inflammatory cells, thereby promoting and maintaining inflammation [27]. In addition to producing pro-inflammatory proteins, macrophages also release anti-inflammatory proteins designed to mitigate the immune response against pathogens, as an excessive inflammatory reaction could lead to self-tissue damage. Based on these findings, the currently accepted paradigm categorizes macrophages into two subtypes: pro-inflammatory or M1 subtype and anti-inflammatory or M2 subtype [28]. 巨噬细胞与中性粒细胞一起，是抵御病原体入侵的主要防御机制。然而，它们的吞噬能力会随着年龄的增长而下降 [25,26]。当巨噬细胞受到炎症刺激时，它们会分泌细胞因子，如肿瘤坏死因子（TNF）、炎症相关白细胞介素（如 IL-1、IL-6、IL-8 和 IL-12）、趋化因子、白三烯和前列腺素，这些物质可增强血管通透性并吸引炎症细胞，从而促进和维持炎症[27]。除了产生促炎蛋白外，巨噬细胞还释放抗炎蛋白，旨在减轻针对病原体的免疫反应，因为过度的炎症反应可能导致自身组织受损。基于这些发现，目前公认的范式将巨噬细胞分为两种亚型：促炎或 M1 亚型和抗炎或 M2 亚型[28]。
M2-activated macrophages release anti-inflammatory cytokines that help regulate M1 pro-inflammatory macrophages, reduce inflammatory responses, and promote injury M2 活化的巨噬细胞会释放抗炎细胞因子，帮助调节 M1 促炎巨噬细胞，减轻炎症反应，促进损伤的愈合
recovery and tissue restoration [29]. While the macrophages’ plasticity is advantageous for wound healing, their response becomes altered in the presence of tumors. The TME alters and reconfigures the immune response, facilitating and maintaining tumor growth. 恢复和组织复原[29]。虽然巨噬细胞的可塑性有利于伤口愈合，但在肿瘤存在的情况下，它们的反应会发生改变。TME改变并重构了免疫反应，促进并维持了肿瘤的生长。
3. Activation of Macrophages 3.激活巨噬细胞
Macrophages have several functions that help maintain immune homeostasis, including tissue repair, phagocytosis, clearance of foreign materials, and the secretion of cytokines and complement proteins. These processes are essential for immune responses to infections and are involved in inflammation. To carry out their protective roles and repair damaged tissues, macrophages display a wide range of surface, vacuolar, and cytosolic receptors, which will facilitate the phagocytosis and endocytosis of viral and bacterial components [4]. 巨噬细胞具有多种功能，有助于维持免疫平衡，包括组织修复、吞噬、清除异物以及分泌细胞因子和补体蛋白。这些过程对于免疫应答感染和参与炎症反应至关重要。为了发挥其保护作用和修复受损组织，巨噬细胞显示出多种表面、空泡和细胞膜受体，这些受体将促进病毒和细菌成分的吞噬和内吞[4]。
Macrophages exhibit a diverse range of functions and characteristics. Their activation into either M1 or M2 phenotypes is known as “polarization”, a biological process that occurs in response to signals received from the surrounding microenvironment [30,31]. This is a crucial process for tissue repair and maintaining homeostasis [28]. M1 polarization is referred to as the “classical” pathway, whereas that of M2 is identified as the “alternative” pathway [32]. M1 macrophages secrete pro-inflammatory cytokines, such as TNF, IL-12, and gamma interferon (IFN- gamma\gamma ), while also producing high amounts of nitric oxide synthase (NOS), which is responsible for converting arginine into nitric oxide (NO) [33,34]. 巨噬细胞具有多种功能和特征。它们被激活成为 M1 或 M2 表型被称为 "极化"，这是一个响应周围微环境信号的生物过程[30,31]。这是组织修复和维持平衡的关键过程[28]。M1 极化被称为 "经典 "途径，而 M2 极化被认为是 "替代 "途径[32]。M1 巨噬细胞分泌促炎细胞因子，如 TNF、IL-12 和γ 干扰素（IFN- gamma\gamma ），同时也产生大量一氧化氮合酶（NOS），该酶负责将精氨酸转化为一氧化氮（NO）[33,34]。
In the presence of lipopolysaccharides (LPSs), macrophages switch their phenotype towards M1 and upregulate CD80, CD86, Toll-like receptor (TLR)-2, and TLR-4 expression. M1 macrophages are controlled by nuclear factor-kappa B (NF-кB), signal transducer and activator of transcription (STAT) (specifically STAT1 and STAT5), and interferon regulatory factor (IRF) family members, including IRF3 and IRF5. The first two represent the primary pathways that drive macrophage polarization, enhancing their antimicrobial and antitumoral functions [18,35,36]. M2 macrophages are CD163-, CD209-, and CD206-positive cells [4,37]. This macrophage subtype is primarily regulated by the STAT6 pathway, IRF4, and peroxisome proliferator-activated receptor gamma (PPAR- gamma\gamma ). STAT6 is considered the most important among them [38]. 在存在脂多糖（LPSs）的情况下，巨噬细胞的表型会转向 M1，并上调 CD80、CD86、Toll 样受体（TLR）-2 和 TLR-4 的表达。M1 巨噬细胞受核因子卡巴 B（NF-кB）、转录信号转导和激活因子（STAT）（特别是 STAT1 和 STAT5）以及干扰素调节因子（IRF）家族成员（包括 IRF3 和 IRF5）的控制。前两者是驱动巨噬细胞极化、增强其抗菌和抗肿瘤功能的主要途径 [18,35,36]。M2 巨噬细胞是 CD163、CD209 和 CD206 阳性的细胞 [4,37]。这种巨噬细胞亚型主要受 STAT6 通路、IRF4 和过氧化物酶体增殖激活受体伽马（PPAR- gamma\gamma ）的调控。STAT6被认为是其中最重要的途径[38]。
Although macrophages are dichotomized as M1 and M2, they are closely interconnected. The regulation of macrophage polarization involves various factors, including the STAT family, PPAR-y, the cAMP-responsive element-binding protein (CREB)-CCAAT/ enhancer-binding protein (C/EBP) axis, IRF, and NF-кB family. This process encompasses numerous signaling molecules, such as JAK/STAT and c- Jun N-terminal kinase (JNK) [39,40]. Table 1 presents the macrophages’ activation and polarization. The M1 and M2 pathways have antithetical functions. M2 macrophages promote cell repair and growth by secreting ornithine, whereas M1 macrophages drive destruction through NO production, which is involved in microbicidal activity and the inhibition of cell proliferation. An imbalance between these two macrophage types can result in metabolic instability, potentially leading to the onset of autoimmune diseases or even cancer [41]. 虽然巨噬细胞被分为 M1 和 M2 两种，但它们之间存在着密切的联系。巨噬细胞极化的调控涉及多种因素，包括 STAT 家族、PPAR-y、cAMP 反应元件结合蛋白（CREB）-CCAAT/增强子结合蛋白（C/EBP）轴、IRF 和 NF-кB 家族。这一过程包括许多信号分子，如 JAK/STAT 和 c- Jun N 端激酶（JNK）[39,40]。表 1 列出了巨噬细胞的活化和极化。M1 和 M2 通路具有相反的功能。M2 巨噬细胞通过分泌鸟氨酸促进细胞修复和生长，而 M1 巨噬细胞则通过产生 NO（参与杀微生物活动和抑制细胞增殖）推动细胞破坏。这两种巨噬细胞之间的失衡会导致新陈代谢不稳定，有可能引发自身免疫性疾病甚至癌症[41]。
The term “alternative activation” has been extended to include new phenotypes, like M2 a/b/c/d [42]. The M2a phenotype is produced in vitro by exposing cells to IL-4 or IL-13, resulting in enhanced levels of CD206, arginase, and transforming growth factor beta\beta (TGF- beta\beta ). Meanwhile, the M2b phenotype is triggered by several IgG and LPS immune complexes, which induce the production of IL-10, while lowering IL-12 levels [43,44]. Macrophages that were exposed in vitro to IL-10 or glucocorticoids induce the M2c phenotype, characterized by increased IL-10, reduced IL-12 levels, and enhanced CD163 surface receptor expression. In contrast, M2d-like macrophages are activated by Toll-like receptors (TLRs) and stimulate IL-10, vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF) production, thus aiding angiogenesis and tumoral progression. Additionally, fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) can facilitate tumor cell development and metastasis, in various cancers, as well as in AML [45,46]. 替代活化 "一词已扩展到包括新的表型，如 M2 a/b/c/d [42]。M2a表型是通过将细胞暴露于IL-4或IL-13，导致CD206、精氨酸酶和转化生长因子 beta\beta （TGF- beta\beta ）水平升高而在体外产生的。同时，几种 IgG 和 LPS 免疫复合物会触发 M2b 表型，诱导产生 IL-10，同时降低 IL-12 水平 [43,44]。体外暴露于IL-10或糖皮质激素的巨噬细胞会诱导M2c表型，其特点是IL-10增加，IL-12水平降低，CD163表面受体表达增强。相反，M2d 样巨噬细胞会被 Toll 样受体（TLRs）激活，刺激 IL-10、血管内皮生长因子（VEGF）和表皮生长因子（EGF）的产生，从而帮助血管生成和肿瘤进展。此外，成纤维细胞生长因子（FGF）和血小板衍生生长因子（PDGF）可促进各种癌症以及急性髓细胞性白血病中肿瘤细胞的发展和转移 [45,46]。
In summary, macrophages can adopt various phenotypes in reaction to different stimuli. 总之，巨噬细胞可以对不同的刺激做出不同的表型反应。
Table 1. Macrophage differentiation and polarization. 表 1.巨噬细胞的分化和极化
Monocytes can transform into macrophages (M0), which may then further polarize into either an M1 or M2 phenotype. In response to LPS and IFN- gamma\gamma, the M1 subtype releases pro-inflammatory cytokines while also producing iNOS, thus contributing to inflammation, cytotoxicity, and tumor destruction. Alternatively, monocytes can be polarized into M2 macrophages under the effect of IL-4 and IL-13. M2 macrophages secrete IL-10, TGF- beta\beta, and Arg1, which impart immunosuppressive and pro-tumorigenic effects. An imbalance between M1 and M2 macrophages creates a microenvironment conducive to tumor progression. 单核细胞可转化为巨噬细胞（M0），然后可进一步极化为 M1 或 M2 表型。在对 LPS 和 IFN- gamma\gamma 作出反应时，M1 亚型会释放促炎细胞因子，同时产生 iNOS，从而促进炎症、细胞毒性和肿瘤破坏。另外，在 IL-4 和 IL-13 的作用下，单核细胞可极化为 M2 巨噬细胞。M2 巨噬细胞会分泌 IL-10、TGF- beta\beta 和 Arg1，从而产生免疫抑制和促肿瘤作用。M1 和 M2 巨噬细胞之间的失衡会造成有利于肿瘤发展的微环境。
4. Tumor-Associated Macrophages 4.肿瘤相关巨噬细胞
The emergence of various cancer types, including leukemia, is not solely due to genetic and epigenetic alterations; it also involves pathological changes in the microenvironment, including the stroma and its cellular components [47]. For instance, tumor cells can evade immune responses, causing stromal and immune cells-typically responsible for defending the host against harmful threats-to secrete anti-inflammatory cytokines. These cytokines ultimately protect the tumor cells and facilitate their growth and proliferation [48,49]. As previously noted, macrophages that invade tumor tissues or the TME are referred to as TAMs. TAMs significantly contribute to tumor progression by fostering genetic instability and metastasis, and they also participate in the suppression of adaptive immunity [50]. Most TAMs are present in avascular areas [51,52]. 包括白血病在内的各种癌症类型的出现并不完全是由于基因和表观遗传学的改变，它还涉及微环境的病理变化，包括基质及其细胞成分 [47]。例如，肿瘤细胞可以逃避免疫反应，导致基质细胞和免疫细胞--通常负责保护宿主免受有害威胁--分泌抗炎细胞因子。这些细胞因子最终会保护肿瘤细胞，并促进其生长和增殖 [48,49]。如前所述，侵入肿瘤组织或 TME 的巨噬细胞被称为 TAMs。TAMs 通过促进遗传不稳定性和转移，对肿瘤的进展起着重要作用，它们还参与抑制适应性免疫[50]。大多数 TAMs 存在于无血管区域 [51,52]。
In individuals diagnosed with breast, ovarian, or prostate cancers, TAMs are elevated, particularly of the M2 subtype, which has been associated with faster tumor progression, metastasis, and reduced response to treatment. Conversely, in lung cancer, a higher presence of M1 macrophages has been associated with more favorable outcomes due to their capacity to hinder tumor progression and enhance the effects of chemotherapy [53]. In colorectal cancer, TAMs seem to exhibit controversial roles. Certain research indicates that a higher presence of macrophages may be linked to improved outcomes, whereas other findings suggest the opposite. One possible explanation for this discrepancy is that TAMs can be found both within and outside the tumor, and their functions may vary based on their location [54]. Recent investigations revealed that M2 macrophages are more prevalent than the M1 subtype in lung tumors, while M1 macrophages are predominant in colon carcinomas. In the context of lung cancer, M2 macrophages facilitate cell invasion and tumor development, unlike M1 macrophages, which inhibit cell growth, decrease angiogenesis, and trigger apoptosis in lung cancer cells [55-58]. 在确诊为乳腺癌、卵巢癌或前列腺癌的患者中，TAMs 增高，尤其是 M2 亚型，这与肿瘤进展加快、转移和治疗反应减弱有关。相反，在肺癌中，由于 M1 型巨噬细胞能够阻碍肿瘤进展并增强化疗效果，因此 M1 型巨噬细胞越多，预后越好 [53]。在结直肠癌中，TAMs 的作用似乎存在争议。某些研究表明，巨噬细胞越多，预后越好，而其他研究结果则相反。对这种差异的一种可能解释是，TAMs 在肿瘤内外均可发现，其功能可能因位置而异 [54]。最近的研究发现，在肺癌中，M2 巨噬细胞比 M1 亚型更普遍，而在结肠癌中，M1 巨噬细胞则占主导地位。在肺癌中，M2 巨噬细胞有助于细胞侵袭和肿瘤发展，而 M1 巨噬细胞则不同，它能抑制细胞生长、减少血管生成并引发肺癌细胞凋亡 [55-58]。
LAMs/TAMs’ phenotypic and functional traits differ based on the unique microenvironments found in different organs [57]. It remains unclear which factors contribute to altering macrophage polarization, promoting the growth of cancerous cells rather than suppressing their proliferation [59]. When TAMs are polarized as the M1 subtype, they function as pro-inflammatory and antitumor cells. In contrast, a transition to the M2 phenotype reveals tumor-nurturing attributes; their presence is linked to a poor prognosis [60]. The development of pro-tumorigenic TAMs depends on elements that promote macrophage expansion as well as factors that trigger their polarization [61]. The infiltration of macrophages in the TME is regulated by CCL2, CCL5, CCL7 and CX3CL1 chemokines, in addition to VEGF [62,63][62,63]. LAMs/TAMs 的表型和功能特征因不同器官的独特微环境而异 [57]。目前仍不清楚哪些因素导致巨噬细胞极化改变，促进癌细胞的生长而不是抑制其增殖 [59]。当 TAMs 极化为 M1 亚型时，它们具有促炎和抗肿瘤细胞的功能。与此相反，向 M2 表型的转变则显示出肿瘤培育属性；它们的存在与不良预后有关 [60]。促肿瘤性 TAMs 的发展取决于促进巨噬细胞扩张的因素以及引发其极化的因素 [61]。除血管内皮生长因子 [62,63][62,63] 外，巨噬细胞在TME中的浸润还受CCL2、CCL5、CCL7和CX3CL1趋化因子的调控。
In the TME, there are interactions among TAMs and cancer and stromal cells. Factors secreted by the tumor cells, including IL4, IL10, and stromal-derived factors, lead to a transition towards the M2 subtype and attract new macrophages and inflammatory cells [64,65]. 在TME中，TAMs与癌细胞和基质细胞之间存在相互作用。肿瘤细胞分泌的因子（包括 IL4、IL10 和基质衍生因子）会导致向 M2 亚型过渡，并吸引新的巨噬细胞和炎症细胞 [64,65]。
After recruitment and polarization, TAMs can contribute to tumor progression, metastasis, resistance to chemotherapy, and immune evasion [66]. Once macrophages accumulate in the TME, several cytokines produced by the tumor or stromal cells initiate the tumornurturing transformation of TAMs. IL-4 and IL-13 act on TAMs through STAT6 and phosphoinositide-3-kinase (PI3K) pathways. Additionally, IL-10 released from Tregs promotes the M2 polarization of TAMs via STAT3 activation. Factors secreted by macrophages that contribute to tumor progression include ornithine, VEGF, EGF, and TGF- beta\beta. In contrast, NO generated from ROS within macrophages can inhibit tumor growth [67]. 巨噬细胞被招募和极化后，可促进肿瘤进展、转移、抗化疗和免疫逃避 [66]。一旦巨噬细胞聚集在 TME 中，肿瘤或基质细胞产生的几种细胞因子就会启动 TAMs 的肿瘤培育转化。IL-4 和 IL-13 通过 STAT6 和磷酸肌醇-3-激酶（PI3K）途径作用于 TAMs。此外，Tregs 释放的 IL-10 可通过 STAT3 激活促进 TAMs 的 M2 极化。巨噬细胞分泌的有助于肿瘤进展的因子包括鸟氨酸、血管内皮生长因子、EGF 和 TGF- beta\beta 。相反，巨噬细胞内的 ROS 生成的 NO 可抑制肿瘤生长 [67]。
As mentioned above, the polarization of TAMs is induced by several cytokines, chemokines, growth factors, and tumor and stromal cells [68]. Colony-stimulating factor (CSF-1) and CC motif ligand 2 (CCL2) represent some of the most extensively researched factors that stimulate M2-type macrophages [69]. CSF-1 plays a critical role in facilitating the harvesting of monocytes from the peripheral blood, guiding them through their maturation process, and pushing their polarization towards the M2 subtype, through its interaction with the CSF-1R receptor. CSF-R1 signaling pathways are essential for controlling the differentiation, proliferation, and survival of macrophages and their precursors, monocytes. Recent studies indicate that signaling through CSF-1/1R within tumors may enhance TAM2’s recruitment and foster an anti-inflammatory environment, ultimately aiding in tumor progression and metastasis. CSF-1 exhibits both autocrine and paracrine effects within the tumor milieu, underscoring its involvement in tumor growth. CCL2 facilitates the polarization of macrophages towards the M2 phenotype, which is associated with tumor growth stimulation by engaging the CC2 chemokine receptor (CCR2) from the macrophage surface [68]. In tumor-bearing mouse models, blocking the CCL2-CCR2 interaction led to extended survival and reduced levels of pro-tumorigenic cytokines [4,70,71]. Figure 1 presents TAMs and their functions. 如上所述，TAMs 的极化是由多种细胞因子、趋化因子、生长因子以及肿瘤和基质细胞诱导的[68]。集落刺激因子（CSF-1）和 CC motif ligand 2（CCL2）是研究最广泛的刺激 M2 型巨噬细胞的因子之一[69]。CSF-1 通过与 CSF-1R 受体相互作用，在促进从外周血中收集单核细胞、引导它们完成成熟过程以及推动它们向 M2 亚型极化方面发挥着关键作用。CSF-R1 信号通路对于控制巨噬细胞及其前体单核细胞的分化、增殖和存活至关重要。最近的研究表明，肿瘤内通过 CSF-1/1R 发出的信号可能会增强 TAM2 的招募，并形成一种抗炎环境，最终有助于肿瘤的进展和转移。CSF-1 在肿瘤环境中表现出自分泌和旁分泌效应，突出表明它参与了肿瘤的生长。CCL2 通过与巨噬细胞表面的 CC2 趋化因子受体（CCR2）结合，促进巨噬细胞向 M2 表型极化，从而刺激肿瘤生长 [68]。在肿瘤小鼠模型中，阻断 CCL2-CCR2 相互作用可延长生存期并降低促肿瘤细胞因子的水平 [4,70,71]。图 1 介绍了 TAMs 及其功能。
Figure 1. TAMs and their functions: M1-like macrophages have antitumor effects and are activated by inflammatory cytokines. These macrophages produce chemokines like CXCL10, which play a crucial role in attracting and activating T cells. Additionally, M1-like macrophages actively phagocytose 图 1.TAMs 及其功能：M1 样巨噬细胞具有抗肿瘤作用，并被炎症细胞因子激活。这些巨噬细胞会产生 CXCL10 等趋化因子，在吸引和激活 T 细胞方面发挥重要作用。此外，M1 样巨噬细胞还能积极吞噬
cancer cells while releasing TNF- alpha\alpha, ROS, and NO to target and eliminate neoplastic cells. In contrast, M2-like macrophages serve pro-tumor roles; they secrete factors that enhance and promote tumor growth. Furthermore, they produce immune-suppressive substances, which support the function of regulatory T cells. Abbreviations: TAMs = Tumour-associated macrophages; APCs = Antigenpresenting cells; TNF = Tumor necrosis factor; IL = Interleukin; CXCL = Chemokine (C-X-C motif) ligand; INF = Interferon; NO = Nitrogen oxide; ROS=\mathrm{ROS}= Reactive oxygen species; PD=\mathrm{PD}= Programmed death; PDL = Programmed death ligand; TGF = Transforming growth factors; MMPs = Matrix metalloproteinases; EGF = Epidermal growth factor; FGF = Fibroblast growth factor; PDGF = Plateletderived growth factor; VEGF = Vascular endothelial growth factor. M2 样巨噬细胞在释放 TNF- alpha\alpha 、ROS 和 NO 的同时，还能靶向消灭肿瘤细胞。与此相反，M2 样巨噬细胞具有促肿瘤作用；它们分泌的因子可增强和促进肿瘤生长。此外，它们还产生免疫抑制物质，支持调节性 T 细胞的功能。缩写：TAMs=肿瘤相关巨噬细胞；APCs=抗原递呈细胞；TNF=肿瘤坏死因子；IL=白细胞介素；CXCL=趋化因子（C-X-C motif）配体；INF=干扰素；NO=氧化氮； ROS=\mathrm{ROS}= 活性氧； PD=\mathrm{PD}= 程序性死亡；PDL=程序性死亡配体；TGF=转化生长因子；MMPs=基质金属蛋白酶；EGF=表皮生长因子；FGF=成纤维细胞生长因子；PDGF=血小板衍生生长因子；VEGF=血管内皮生长因子。
Several studies indicate that TAMs can drive cancer cells to develop treatment resistance by enhancing the properties of cancer stem cells (CSCs), which play a role in the emergence of tumor angiogenesis [72-75]. Furthermore, TAMs produce cytokines and chemokines, including IL-6 and CCL18, which contribute to the development of therapeutic resistance [54]. TAMs induce resistance to immunotherapy by impeding T-cell functions. Within the TME, TAMs interact with other cells, promoting tumor growth and contributing to chemoresistance. Despite their various roles in the microenvironments of hematological malignancies, the significance of TAMs as diagnostic and potentially prognostic markers is still not fully understood, although emerging studies indicate promising findings [76,77]. While TAMs in the TME appear to facilitate tumor proliferation and progression, their mechanisms of action may differ depending on the specific disease context [40,67]. 一些研究表明，TAMs 可通过增强癌症干细胞（CSCs）的特性来促使癌细胞产生耐药性，而癌症干细胞在肿瘤血管生成过程中发挥着作用[72-75]。此外，TAMs 还会产生细胞因子和趋化因子，包括 IL-6 和 CCL18，这有助于抗药性的产生 [54]。TAMs 通过阻碍 T 细胞功能诱导免疫疗法的抗药性。在TME内，TAMs与其他细胞相互作用，促进肿瘤生长并导致化疗耐药。尽管 TAMs 在血液恶性肿瘤的微环境中发挥着各种作用，但其作为诊断和潜在预后标志物的意义仍未完全明了，尽管新的研究表明其前景看好 [76,77]。虽然 TME 中的 TAMs 似乎促进了肿瘤的增殖和进展，但其作用机制可能因具体疾病而异 [40,67]。
Chimeric antigen receptor T cells (CAR-Ts) are a form of cellular therapy that was FDA-approved for hematological malignancy treatment. However, the absence of indications for this type of therapy in AML and other solid tumors led to the development of CAR-natural killer cells (CAR-NKs) and CAR-macrophage cells (CAR-Ms) [78]. CARMs are developed to enhance the macrophages’ capacity to trigger innate immunity and phagocytize tumor cells. In 2020, the first clinical trial employing CAR-Ms as a therapy for HER2-positive solid tumors was launched. Further, the technology was developed to address lymphoproliferative disorders as well, with a good safety profile [79]. However, to date, no efficacy of CAR-Ms in AML has been proven. 嵌合抗原受体 T 细胞（CAR-Ts）是一种细胞疗法，已获美国食品及药物管理局批准用于血液恶性肿瘤治疗。然而，由于这种疗法在急性髓细胞性白血病和其他实体瘤中缺乏适应症，人们开发出了CAR-自然杀伤细胞（CAR-NKs）和CAR-巨噬细胞（CAR-Ms）[78]。CARMs 的开发旨在增强巨噬细胞触发先天免疫和吞噬肿瘤细胞的能力。2020 年，首个采用 CAR-Ms 治疗 HER2 阳性实体瘤的临床试验启动。此外，该技术还被开发用于治疗淋巴增生性疾病，并具有良好的安全性[79]。不过，迄今为止，CAR-Ms 对急性髓细胞性白血病的疗效尚未得到证实。
5. M2 Macrophages in AML 5.AML 中的 M2 巨噬细胞
In the context of AML, LAMs are essential contributors to therapeutic resistance and leukemia cells’ protection from apoptosis induced by cytarabine [5]. The main goal of macrophage-targeted therapy in neoplastic disease is to reduce the population of anti-inflammatory macrophages while enhancing the presence of pro-inflammatory macrophages that support antitumor activity [80]. 就急性髓细胞性白血病而言，巨噬细胞是导致抗药性和保护白血病细胞免受阿糖胞苷诱导的细胞凋亡的重要因素[5]。在肿瘤性疾病中，巨噬细胞靶向治疗的主要目标是减少抗炎巨噬细胞的数量，同时增加支持抗肿瘤活性的促炎巨噬细胞的数量[80]。
Macrophage invasion in the TME has been recognized as a poor prognostic indicator in various cancers, including leukemias [81]. There is growing interest in immunotherapies that target TAMs/LAMs [80]. These therapies inhibit their pro-tumor signaling, restore their immune-stimulating functions, and deplete TAMs [74,82]. With an enhanced understanding of the role of macrophages in hematological cancers, potential strategies for targeting LAMs have been proposed and investigated for therapeutic use [83]. 在包括白血病在内的多种癌症中，TME 中巨噬细胞的侵袭已被视为预后不良的指标[81]。针对 TAMs/LAMs 的免疫疗法越来越受到关注 [80]。这些疗法可抑制其促瘤信号传导，恢复其免疫刺激功能，并消耗 TAMs [74,82]。随着人们对巨噬细胞在血液肿瘤中作用的进一步了解，针对 LAMs 的潜在治疗策略也被提出并进行了研究 [83]。
The PI3K-AKT-mTOR signaling pathway shows abnormal regulation in individuals diagnosed with AML, as a result of various molecular mutations, including FTL3-ITD. This alteration is present in almost 30%30 \% of AML patients and has been linked to poorer survival outcomes [84,85]. Class I PI3K is made up of the p85 regulatory subunit and the four isoforms of the p110 subunits: alpha,beta,gamma\alpha, \beta, \gamma, and delta\delta. AML blasts consistently express the p110 delta\delta isoform [86]. Targeting both PI3K gamma\gamma and PI3K delta\delta with the selective inhibitor IPI-145 has shown a decrease in AML blast survival, secondary to the inhibition of AKT survival pathways, and also by affecting macrophage polarization [87,88]. mTOR signaling is essential for macrophage polarization, and research showed that the inhibition of mTORC2 stimulates the shift of macrophages towards the M2 subtype, whereas the mTORC1 blockade enhances M1 macrophage function [89,90]. However, mTOR inhibitors did not show spectacular results in AML treatment in clinical and preclinical studies [91,92]. 在确诊为急性髓细胞性白血病的患者中，PI3K-AKT-mTOR 信号通路因各种分子突变（包括 FTL3-ITD）而出现异常调节。几乎 30%30 \% 的急性髓细胞性白血病患者都存在这种改变，并与较差的生存结果有关 [84,85]。I 类 PI3K 由 p85 调节亚基和 p110 亚基的四种异构体组成： alpha,beta,gamma\alpha, \beta, \gamma 和 delta\delta 。急性髓细胞白血病持续表达 p110 delta\delta 异构体 [86]。用选择性抑制剂 IPI-145 靶向 PI3K gamma\gamma 和 PI3K delta\delta 可降低 AML 病灶的存活率，这是由于 AKT 生存通路受到抑制，同时也影响了巨噬细胞的极化 [87,88]。研究表明，抑制 mTORC2 会刺激巨噬细胞向 M2 亚型转移，而阻断 mTORC1 则会增强 M1 型巨噬细胞的功能 [89,90]。然而，在临床和临床前研究中，mTOR 抑制剂在治疗急性髓细胞性白血病方面并未显示出惊人的效果 [91,92]。
Rather than using macrophages as direct targets, focusing on their re-education seems a good therapeutic strategy. This is supported by Mussai et al., who proved that the production of arginase II by AML blasts induces the reprogramming of immunocompetent donor monocytes into the anti-inflammatory macrophage subtype [93]. Bone marrow samples of AML patients were assessed by immunohistochemical analysis that revealed an enhanced CD206+ cell level, which are associated with M2 polarization of macrophages [94]. Research conducted by AL-Matary et al. employed various mouse models of AML, including transgenic models featuring mutations like NUP98-HOXD13. Their findings indicated that M2-like macrophage levels were elevated in the bone marrow of leukemic mouse models compared to those without leukemia. In particular, studies on the NUP98-HOXD13 mouse model, which mimics t(2;11)(q31;p15), revealed a negative correlation between the elevated percentage of alternatively activated macrophages (AAMs) in these mice and their survival rates [95]. Among AML patients, researchers have noticed a reduction in the amount of monocytic leukemia zinc finger protein (MOZ), which plays a role in the macrophage development cycle, by interacting with miR-223. In contrast, miR-223 levels were significantly elevated when compared to those in clinically and biologically healthy individuals. Furthermore, actual research correlated low MOZ expression with the monocytic subtype of AML [95]. 与其将巨噬细胞作为直接靶点，不如将重点放在其再教育上，这似乎是一种很好的治疗策略。这一点得到了 Mussai 等人的支持，他们证明了急性髓细胞白细胞产生的精氨酸酶 II 能诱导免疫功能正常的供体单核细胞重编程为抗炎巨噬细胞亚型 [93]。通过免疫组化分析评估急性髓细胞性白血病患者的骨髓样本，发现CD206+细胞水平升高，这与巨噬细胞的M2极化有关[94]。AL-Matary 等人的研究采用了多种急性髓细胞性白血病小鼠模型，包括具有 NUP98-HOXD13 等突变的转基因模型。他们的研究结果表明，与未患白血病的小鼠相比，白血病小鼠骨髓中的 M2 样巨噬细胞水平升高。特别是对模拟 t(2;11)(q31;p15)的 NUP98-HOXD13 小鼠模型的研究显示，这些小鼠中替代性活化巨噬细胞（AAMs）比例的升高与它们的存活率呈负相关[95]。研究人员注意到，在急性髓细胞性白血病患者中，单核细胞白血病锌指蛋白（MOZ）的数量有所减少，而该蛋白通过与 miR-223 相互作用，在巨噬细胞发育周期中发挥作用。相反，与临床和生物学健康个体相比，miR-223 水平明显升高。此外，实际研究表明，MOZ 的低表达与急性髓细胞性白血病的单核细胞亚型相关[95]。
The precise macrophage function in resistance to treatment remains incompletely understood. Macrophages secrete substances that activate the extracellular signal-regulated kinase pathways 1 and 2 (ERK1/2) and regulate MCL-1 protein expression [96]. 巨噬细胞在抗药性中的确切功能仍不完全清楚。巨噬细胞分泌的物质可激活细胞外信号调节激酶通路 1 和 2（ERK1/2），并调节 MCL-1 蛋白的表达 [96]。
M2-like macrophages consistently produce increased amounts of CCL2. Research has shown that in response to its influence, AML blasts will migrate due to their expression of functional CCR2 [97]. CCL2 is considered a prognostic indicator for AML, as elevated CCL2 levels in untreated AML patients were associated with poor cytogenetic profiles and, thus, with an unfavorable prognosis [98-100]. M2 样巨噬细胞会持续产生更多的 CCL2。研究表明，在它的影响下，急性髓细胞白细胞会因表达功能性 CCR2 而迁移 [97]。CCL2 被认为是急性髓细胞性白血病的一个预后指标，因为未经治疗的急性髓细胞性白血病患者 CCL2 水平升高与细胞遗传学特征不良有关，因此与预后不良有关 [98-100]。
In AML patients, high serum levels of chitinase-3-like (CHI3L) were linked to a poor prognosis [101,102]. In ovarian cancer, CHI3L1 plays a role in activating the extracellular signal-regulated kinase (ERK) 1/2 pathway, which enhances resistance to chemotherapy by increasing the level of MCL-1 protein [103]. Additionally, research indicates a significant relationship between CHI3L and the M2 polarization of macrophages [104]. 在急性髓细胞性白血病患者中，血清中几丁质酶-3-样（CHI3L）水平高与预后不良有关 [101,102]。在卵巢癌中，CHI3L1 起着激活细胞外信号调节激酶（ERK）1/2 通路的作用，通过增加 MCL-1 蛋白水平增强对化疗的抵抗力 [103]。此外，研究表明 CHI3L 与巨噬细胞的 M2 极化之间存在重要关系 [104]。
6. Therapeutic Targets of Macrophages 6.巨噬细胞的治疗目标
The standard treatment for young and fit patients with AML who can handle intensive therapy is the " 3+73+7 " regimen, which combines an anthracycline with cytarabine. However, the current results of this treatment regimen are not entirely satisfying. Immunotherapy presents a promising alternative for managing both solid and blood tumors. It may provide a less aggressive and better-tolerated option for treating AML, with the potential to elicit more durable responses and improve life expectancy [105]. 对于身体健康、可以接受强化治疗的年轻急性髓细胞性白血病患者来说，标准治疗方法是" 3+73+7 "方案，该方案将蒽环类药物与阿糖胞苷结合在一起。然而，目前这种治疗方案的效果并不完全令人满意。免疫疗法是治疗实体瘤和血液肿瘤的一种很有前途的选择。它可能为治疗急性髓细胞性白血病提供一种侵袭性较低且耐受性较好的选择，并有可能产生更持久的反应和延长预期寿命[105]。
AML cells can establish mechanisms to effectively evade cell death, such as inhibiting NK cells or downregulating specific surface receptors. Concurrently, they enhance the expression of inhibitory immune checkpoints, such as programmed death ligands (PD-L1 and PD-L2), CD47 and CD 70 [106-108]. 急性髓细胞性白血病细胞可建立有效逃避细胞死亡的机制，如抑制 NK 细胞或下调特定表面受体。同时，它们会增强抑制性免疫检查点的表达，如程序性死亡配体（PD-L1 和 PD-L2）、CD47 和 CD 70 [106-108]。
Under physiological circumstances, programmed cell death protein 1 (PD-1) is present on activated T cells and B cells as well as regulatory T cells (Tregs). PD-1 acts to prevent excessive immune activation by binding to its receptors, PD-L1 and PD-L2, expressed on macrophages and dendritic cells. This interaction generally allows tumors to evade the immune response by inhibiting T-cell activity and blocking cytokine signaling, while simultaneously providing an anti-apoptotic signal to tumor cells via PD-L1. Consequently, PD-1/PD-L1/PD-L2 inhibitors-known as checkpoint inhibitors-have shown substantial efficacy in treating Hodgkin’s lymphoma, although their impact in AML treatment was considerably lower [109,110]. The differences between M1 and M2 subsets of macrophages may be associated with important factors, including disease severity and the timing of diagnosis. The presence of high levels of the anti-inflammatory macrophage subtype in 在生理情况下，活化的 T 细胞和 B 细胞以及调节性 T 细胞（Tregs）上都存在程序性细胞死亡蛋白 1（PD-1）。PD-1 与巨噬细胞和树突状细胞上表达的受体 PD-L1 和 PD-L2 结合，防止免疫过度激活。这种相互作用通常可使肿瘤通过抑制 T 细胞活性和阻断细胞因子信号传导来逃避免疫反应，同时通过 PD-L1 向肿瘤细胞提供抗凋亡信号。因此，PD-1/PD-L1/PD-L2 抑制剂--即检查点抑制剂--在治疗霍奇金淋巴瘤方面显示出了巨大疗效，但在治疗急性髓细胞性淋巴瘤方面的影响要小得多 [109,110]。巨噬细胞 M1 和 M2 亚群之间的差异可能与疾病严重程度和诊断时间等重要因素有关。M1和M2亚群之间的差异可能与疾病的严重程度和诊断时间等重要因素有关。
the bone marrow of patients may be related to their disease evolution and response to checkpoint inhibitors, potentially serving as a prognostic indicator [94,97]. Modulating M2 macrophage expression could improve PD-1/PD-L1 inhibitor treatment outcomes in AML [111]. 患者骨髓中M2巨噬细胞的表达可能与其疾病的演变和对检查点抑制剂的反应有关，有可能成为预后指标[94,97]。调节M2巨噬细胞的表达可改善PD-1/PD-L1抑制剂治疗急性髓细胞白血病的疗效[111]。
Yang et al. demonstrated that AML patients with high CD163 expression levels experienced lower survival rates than those with reduced levels of CD163. Additionally, CD163 is involved in characterizing M2-like macrophages [40]. Another study examined the immunophenotypic characteristics of sixteen AML patients and identified a link between CD163-positive macrophages and unfavorable outcomes. Conversely, the existence M1like macrophages in the TME of AML suggests a more favorable prognosis. The balance between M1 and M2 macrophages could be clinically significant for individuals with AML [112]. The M2 anti-inflammatory macrophages within the TME are typically correlated with a poor prognosis, as patients exhibiting elevated levels of M2 macrophages tend to have reduced survival [72,113][72,113]. Yang等人证实，CD163表达水平高的急性髓细胞性白血病患者的存活率低于CD163表达水平低的患者。此外，CD163 还参与了 M2 样巨噬细胞的特征描述 [40]。另一项研究检查了 16 名急性髓细胞性白血病患者的免疫表型特征，发现 CD163 阳性巨噬细胞与不良预后之间存在联系。相反，急性髓细胞白血病 TME 中存在 M1 样巨噬细胞，则预后较好。M1和M2巨噬细胞之间的平衡对急性髓细胞白血病患者具有重要的临床意义[112]。TME中的M2抗炎巨噬细胞通常与预后不良有关，因为M2巨噬细胞水平升高的患者往往生存率下降 [72,113][72,113] 。
The cells within the TME, particularly LAMs, are vital targets for improving the efficacy of immunotherapy, as they have the ability to suppress the cytotoxic functions of CD8+ T cells and NK cells. Eliminating LAMs could boost the antitumor immune response driven by CD8+ T cells [114]. TME内的细胞，尤其是LAMs，是提高免疫疗法疗效的重要靶点，因为它们能够抑制CD8+ T细胞和NK细胞的细胞毒功能。消除 LAMs 可以增强 CD8+ T 细胞驱动的抗肿瘤免疫反应 [114]。
Therapeutic approaches aimed at M2 macrophages in AML include blocking the recruitment of CCR2+CD14++ CD16- (TAM precursors), the inhibition of CCL2-CCR2 signaling pathways, and reprogramming M1-like macrophages in terms of their function and phenotype [115]. 针对 AML 中 M2 巨噬细胞的治疗方法包括阻断 CCR2+CD14++ CD16-（TAM 前体）的招募、抑制 CCL2-CCR2 信号通路以及从功能和表型方面对 M1 样巨噬细胞进行重编程 [115]。
Currently, selective inhibitors of the p110 delta PI3K isoform are undergoing preclinical development and show promising results for patients with AML. These inhibitors have the ability to reduce macrophage invasion into tumors and shift macrophages towards an M1-like phenotype, but may also have an impact on AML blasts [88]. 目前，p110 delta PI3K 同工酶的选择性抑制剂正在进行临床前开发，对急性髓细胞性白血病患者的治疗效果很好。这些抑制剂能够减少巨噬细胞对肿瘤的侵袭，并使巨噬细胞向 M1 样表型转变，但也可能对急性髓细胞白血病患者产生影响 [88]。
Another therapeutic approach involves the depletion of TAMs. The cytokine CSF-1 plays an essential role in the resilience and evolution of phagocytic cells that express the CSF-R1 receptor. Increased CSF-1 levels or overexpression of CSF-1R have been associated with unfavorable outcomes in Hodgkin’s lymphoma and hepatocellular carcinoma [116]. The pharmacological inhibition of the CSF-1/CSF-1R pathway has been investigated in both preclinical and clinical settings, whether used alone or in combination with other therapies. Targeting CSF-1R to reduce macrophages has led to increased migration of CD8+ cytotoxic T cells and improved therapeutic responses in breast and ovarian cancers [117,118]. 另一种治疗方法是消耗 TAMs。细胞因子 CSF-1 在表达 CSF-R1 受体的吞噬细胞的复原和进化过程中发挥着重要作用。CSF-1 水平的升高或 CSF-1R 的过度表达与霍奇金淋巴瘤和肝细胞癌的不良预后有关 [116]。无论是单独使用还是与其他疗法联合使用，对 CSF-1/CSF-1R 通路的药理抑制已在临床前和临床环境中进行了研究。以 CSF-1R 为靶点减少巨噬细胞可增加 CD8+ 细胞毒性 T 细胞的迁移，改善乳腺癌和卵巢癌的治疗反应 [117,118]。
CSF-1R targeted therapies are employed to prevent the dimerization of the receptors and decrease the survival of macrophages. Research in both clinical and preclinical studies has proven that modulating the CSF/CSF-1R pathway offers a promising avenue for therapy. CSF-1R inhibition leads to better outcomes for patients with advanced cancer and enhances the effectiveness of immunotherapy and chemotherapy [119]. Pexidartinib (PLX3397) is the most extensively researched compound, functioning as an oral inhibitor of the CSF-1R tyrosine kinase. One study indicated that administering PLX3397 to mouse models with breast tumors resulted in a significant reduction in macrophages and tumor development inhibition [120]. CSF-1R 靶向疗法可防止受体二聚化，降低巨噬细胞的存活率。临床和临床前研究证明，调节 CSF/CSF-1R 通路是一种很有前景的治疗方法。抑制 CSF-1R 可以改善晚期癌症患者的预后，提高免疫疗法和化疗的疗效 [119]。Pexidartinib（PLX3397）是研究最为广泛的化合物，它是一种口服的CSF-1R酪氨酸激酶抑制剂。一项研究表明，对患有乳腺肿瘤的小鼠模型施用 PLX3397 后，巨噬细胞显著减少，肿瘤发展受到抑制 [120]。
In a phase-1 study, PLX3397 could be administered alongside other treatments, such as binimetinib, which is indicated for gastrointestinal stromal tumors, and paclitaxel, indicated in advanced ovarian cancer treatment. These associations show significant clinical effectiveness and are generally well tolerated by patients [121,122]. Although depletion of TAMs seems to be a promising strategy for many types of cancer, it should be used selectively, as long-term administration can have detrimental effects. Prolonged inhibition of CSF-1R leads to resistance development and the recurrence of tumors [116]. 在一项 1 期研究中，PLX3397 可与其他治疗药物同时使用，如适用于胃肠道间质瘤的 Binimetinib 和适用于晚期卵巢癌治疗的紫杉醇。这些联合用药显示出明显的临床疗效，而且患者的耐受性普遍良好[121,122]。尽管消耗 TAMs 似乎是治疗多种类型癌症的一种有前途的策略，但应有选择地使用，因为长期用药会产生有害影响。长期抑制 CSF-1R 会导致耐药性的产生和肿瘤的复发 [116]。
Another CSF-1R inhibitor is edicotinib, which is used in prostate cancer therapy, without significant alterations in the CSF-1R+ immune cell population [123]. In 2021, a phase-two clinical trial was initiated for patients with relapsed/refractory AML receiving 另一种CSF-1R抑制剂是埃迪科替尼（edicotinib），该药用于前列腺癌治疗，不会明显改变CSF-1R+免疫细胞群[123]。2021 年，一项针对复发/难治性急性髓细胞性白血病患者的二期临床试验开始接受治疗。
edicotinib. As only three patients were enrolled, more data are required to conclude whether this CSF-1R inhibitor is a relevant treatment option for AML [124]. edicotinib。由于只招募了三名患者，因此需要更多的数据才能断定这种CSF-1R抑制剂是否是治疗急性髓细胞性白血病的相关选择[124]。
Trabectedin and bisphosphonates promote apoptosis and can induce macrophage depletion. Trabectedin, an antineoplastic agent used for ovarian cancer, initiates apoptosis by binding DNA, resulting in cell cycle inhibition and the cleavage of double-stranded DNA [125,126]. 曲贝替丁（Trabectedin）和双膦酸盐可促进细胞凋亡并诱导巨噬细胞耗竭。曲贝替丁（Trabectedin）是一种用于治疗卵巢癌的抗肿瘤药物，它通过结合 DNA 启动细胞凋亡，导致细胞周期抑制和双链 DNA 断裂 [125,126]。
Mononuclear phagocytes are vulnerable to recombinant TNF-related apoptosis-inducing ligand (TRAIL) through a caspase-dependent apoptotic pathway. Monocytes and macrophages exhibit highly expressed TRAIL receptors (TRAIL-R1 and TRAIL-R2), making them more responsive to trabectedin administration [127]. 单核吞噬细胞易受重组 TNF 相关凋亡诱导配体（TRAIL）的影响，这是通过一种依赖于 Caspase 的凋亡途径进行的。单核细胞和巨噬细胞表现出高表达的 TRAIL 受体（TRAIL-R1 和 TRAIL-R2），使其对曲贝替丁（Trabectedin）更敏感 [127]。
Studies have described trabectedin as an inducer of caspase-8-dependent apoptosis in TAMs, leading to a selective reduction in monocytes and macrophages in blood circulation and the TME. In biopsy samples from soft tissue sarcoma patients treated with trabectedin, a significant decrease in the density of TAMs and blood vessels was observed [128]. 研究表明，曲贝替丁（trabectedin）可诱导依赖于 Caspase-8 的 TAMs 凋亡，从而有选择性地减少血液循环和 TME 中的单核细胞和巨噬细胞。在接受曲贝替定治疗的软组织肉瘤患者的活检样本中，观察到 TAMs 和血管的密度显著下降 [128]。
Bisphosphonates are absorbed by bone tissue and metabolized by osteoclasts. Since macrophages share the same cell lineage as osteoclasts, they are also targeted by bisphosphonates. These substances exhibit an antitumor effect by inducing apoptosis in tumor cells, boosting immune surveillance through macrophage targeting, inhibiting tumor cell invasion, reducing angiogenesis, and showing synergistic effects when used alongside other cancer treatments [129-131]. 双膦酸盐可被骨组织吸收并被破骨细胞代谢。由于巨噬细胞与破骨细胞的细胞系相同，因此它们也是双膦酸盐的靶标。这些物质通过诱导肿瘤细胞凋亡、通过巨噬细胞靶向增强免疫监视、抑制肿瘤细胞侵袭、减少血管生成，以及与其他癌症疗法同时使用时显示出协同效应，从而发挥抗肿瘤作用 [129-131]。
Another therapeutic strategy in AML leverages macrophages by targeting CD47, a protein that hinders phagocytosis by targeting the alpha\alpha receptor signaling protein on phagocytic cells. CD47 is overexpressed in AML and other malignant hemopathies. Monoclonal antibodies directed against CD47 enable macrophages to engulf and eliminate the AML cells [132,133]. CD47是一种通过靶向吞噬细胞上的 alpha\alpha 受体信号蛋白来阻碍吞噬作用的蛋白质。CD47在急性髓细胞性白血病和其他恶性血液病中过度表达。针对 CD47 的单克隆抗体可使巨噬细胞吞噬并清除 AML 细胞 [132,133]。
In AML, leukemic cells exhibit CD47 on their surface. Elevated levels of CD47 expression in patients with AML appear to correlate with a poor prognosis. Additionally, this heightened expression is particularly evident in AML patients carrying the FLT3 mutation, which is also linked to a worse prognosis [107]. The presence of CD47 on cell surfaces sends an inhibitory signal to macrophages, effectively signaling “do not eat”, which allows cancer cells to dodge immune elimination. As malignant cells express CD47 across various blood-related disorders, numerous anti-CD47 antibodies are under investigation to significantly enhance existing treatment options [134-136]. The “do not eat” signal is mediated by signal regulatory protein alpha (SIRP alpha\alpha ) found on immune cells [134]. Magrolimab is a monoclonal antibody that targets CD47 and blocks the “don’t eat me” signal exerted by the leukemic cells (Figure 2). 在急性髓细胞性白血病中，白血病细胞表面显示 CD47。急性髓细胞性白血病患者 CD47 表达水平升高似乎与预后不良有关。此外，这种高表达在携带 FLT3 基因突变的急性髓细胞性白血病患者中尤为明显，而 FLT3 基因突变也与预后不良有关 [107]。细胞表面 CD47 的存在向巨噬细胞发出抑制信号，有效地发出 "不要吃 "的信号，使癌细胞得以躲避免疫清除。由于恶性细胞在各种血液相关疾病中都表达 CD47，目前正在研究多种抗 CD47 抗体，以大大提高现有治疗方案的效果 [134-136]。不吃 "信号由免疫细胞上的信号调节蛋白α（SIRP alpha\alpha ）介导[134]。Magrolimab 是一种针对 CD47 的单克隆抗体，可阻断白血病细胞发出的 "不要吃我 "信号（图 2）。
Initially, magrolimab was evaluated in a phase-I multicentric trial as a standalone AML treatment. Hypomethylating agents were administered synergically to magrolimab, to induce “eat me” signals in the AML cells, thus stimulating the phagocytic process. The pairing of magrolimab and azacitidine has demonstrated promising efficacy in treating AML and myelodysplastic syndrome (MDS) [137]. In patients with AML harboring TP53 mutations, available treatment options are limited, and the outlook is poor [138]. In a phase-IB trial, the researchers assessed the effectiveness and tolerability of combining magrolimab with the hypomethylating agent azacitidine in 72 patients with AML who have the TP53 mutation [139]. The results were promising for this combination, with a good safety profile [139]. Additionally, the combination of magrolimab with the " 3+73+7 " regimen of low-dose cytarabine in treatment-naïve AML patients was shown to enhance clinical response rates [140]. Nevertheless, the effects of cytotoxic agents need to be closely monitored, as they may non-specifically affect pro-phagocytic signals in normal cells as well as leukemic cells, potentially resulting in toxicities [134,137-141]. Another agent that promotes cell death and may work synergistically with magrolimab is venetoclax [142]. It can convey pro-phagocytic signals. A phase-1 trial evaluated the side effects secondary to dose escalation of magrolimab in patients with relapsed/refractory AML. While the patients remained asymptomatic, they all exhibited anemia due to red blood cell agglutination, as 最初，在一项 I 期多中心试验中，将 Magrolimab 作为一种独立的急性髓细胞白血病治疗方法进行了评估。低甲基化药物与马格列单抗协同作用，诱导 AML 细胞发出 "吃我 "信号，从而刺激吞噬过程。在治疗急性髓细胞性白血病和骨髓增生异常综合征（MDS）方面，magrolimab 和阿扎胞苷的配伍显示出良好的疗效[137]。对于携带 TP53 基因突变的急性髓细胞性白血病患者，现有的治疗方案有限，而且前景不佳 [138]。在一项 IB 期试验中，研究人员评估了在 72 例携带 TP53 突变的急性髓细胞性白血病患者中联合使用 Magrolimab 和低甲基化药物阿扎胞苷的有效性和耐受性[139]。研究结果表明，这种联合疗法安全性良好[139]。此外，在治疗无效的急性髓细胞性白血病患者中，将 Magrolimab 与低剂量阿糖胞苷的" 3+73+7 "方案联合使用，可提高临床反应率 [140]。然而，需要密切监测细胞毒性药物的作用，因为它们可能会非特异性地影响正常细胞和白血病细胞的促吞噬细胞信号，从而可能导致毒性反应[134,137-141]。Venetoclax 是另一种促进细胞死亡并可与 magrolimab 协同作用的药物[142]。它能传递促吞噬细胞信号。一项 1 期试验评估了在复发/难治性急性髓细胞性白血病患者中使用剂量升级后的副作用。虽然患者仍无症状，但他们都因红细胞凝集而出现贫血，因为
CD47 is expressed on red blood cells. Nonetheless, no hemolysis was described [142]. Magrolimab has the potential to work synergistically with tumor-targeting antibodies, as these antibodies can deliver an external pro-phagocytic signal via antibody-dependent cellular phagocytosis facilitated by macrophages [140]. In a phase-3 double-blind randomized trial involving around 432 unfit patients, the efficacy of the magrolimab-azacitidine-venetoclax combination was evaluated in comparison to magrolimab-azacitidine-placebo. Although phase-1 and -2 trials showed encouraging results, the study was halted due to an increased mortality risk, mainly secondary to infections and respiratory failure [143,144]. CD47 在红细胞上表达。尽管如此，并未发现溶血现象[142]。Magrolimab 有可能与肿瘤靶向抗体协同作用，因为这些抗体可以通过巨噬细胞促进的抗体依赖性细胞吞噬作用传递外部促吞噬信号[140]。在一项涉及约 432 名不适合患者的 3 期双盲随机试验中，评估了与 magrolimab-azacitidine-placebo 相比，magrolimab-azacitidine-venetoclax 联合疗法的疗效。尽管 1 期和 2 期试验显示出令人鼓舞的结果，但由于主要继发于感染和呼吸衰竭的死亡风险增加，研究被迫中止 [143,144]。
Figure 2. CD47-SIRP alpha\alpha blockade: AML cells evade immune responses by CD47-SIRP alpha\alpha synergy, which provides a “do not eat me” signal. Blocking CD47-SIRP alpha\alpha interaction with magrolimab will induce direct tumor cell apoptosis, complement-mediated apoptosis, and immune cell phagocytosis [79]. 图 2.CD47-SIRP alpha\alpha 阻断：AML 细胞通过 CD47-SIRP alpha\alpha 协同作用逃避免疫反应，从而发出 "不要吃我 "的信号。用 Magrolimab 阻断 CD47-SIRP alpha\alpha 的相互作用将诱导肿瘤细胞直接凋亡、补体介导的细胞凋亡和免疫细胞的吞噬作用 [79]。
Evorpacept (ALX148) (ClinicalTrials.gov identifier: NCT04755244) targets CD47 and was administered in combination with azacitidine and venetoclax in a phase-1/2 clinical trial. The initial results show that an anti-leukemic effect was obtained, with a good safety profile. Further evaluation is necessary [145]. Evorpacept (ALX148)（ClinicalTrials.gov标识符：NCT04755244）以CD47为靶点，在一项1/2期临床试验中与阿扎胞苷和venetoclax联合用药。初步结果显示，该药具有抗白血病的效果，且安全性良好。有必要进行进一步评估 [145]。
CC-90002, a CD47-SIRP alpha\alpha axis inhibitor, was administered as a single-agent therapy in patients with relapsed/refractory AML and high-risk MDS (ClinicalTrials.gov identifier: NCT02641002). However, the study was halted, as no relevant therapeutic response was observed [146]. CC-90002是一种CD47-SIRP alpha\alpha 轴抑制剂，曾作为单药疗法用于复发/难治性AML和高危MDS患者（ClinicalTrials.gov标识符：NCT02641002）。然而，由于没有观察到相关的治疗反应，该研究被终止了[146]。
Hu5F9-G4 was administered as a monotherapy or in combination with azacitidine, as a CD47 inhibitor, in a phase-1 clinical trial (ClinicalTrials.gov identifier: NCT03248479). This immune checkpoint inhibitor showed encouraging results, inducing a strong anti-leukemic effect with a good safety profile [147]. 在一项 1 期临床试验（ClinicalTrials.gov 识别码：NCT03248479）中，Hu5F9-G4 作为一种单药或与作为 CD47 抑制剂的阿扎胞苷联合使用。这种免疫检查点抑制剂取得了令人鼓舞的结果，具有很强的抗白血病效果和良好的安全性[147]。
AUR103 calcium (ClinicalTrials.gov identifier: NCT05607199), TQB2928 (ClinicalTrials.gov identifier: NCT06008405), and AK117 (ClinicalTrials.gov identifier: NCT06387420) are other CD47 antagonists that are currently under evaluation in phase- 1 and phase-1b/2 clinical trials, in association with azacitidine or azacitidine and venetoclax in patients with AML and MDS [148-150]. AUR103钙（ClinicalTrials.gov标识符：NCT05607199）、TQB2928（ClinicalTrials.gov标识符：NCT06008405）和AK117（ClinicalTrials.gov标识符：NCT06387420）是目前正在进行1期和1b/2期临床试验评估的其他CD47拮抗剂，它们与阿扎胞苷或阿扎胞苷和venetoclax联合用于急性髓细胞性白血病和MDS患者[148-150]。
CD47’s overexpression in cancer cells makes it a compelling target for neoplastic disease treatment. Antibodies against CD47 have demonstrated promising results in AML/MDS treatment. Nevertheless, side effects linked to CD47-targeting treatments, such as cytopenia and hyperbilirubinemia, raise significant concerns that must be addressed [142]. CD47 在癌细胞中的过度表达使其成为治疗肿瘤疾病的一个引人注目的靶点。针对 CD47 的抗体在急性髓细胞白血病/骨髓增生异常综合症的治疗中取得了良好的效果。然而，与 CD47 靶向治疗相关的副作用（如全血细胞减少和高胆红素血症）引起了人们的极大关注，必须加以解决 [142]。
Apart from those already mentioned, new immune checkpoint inhibitors are being investigated, such as bexmarilimab (BEX). This drug targets the scavenger receptor Clever1 , leading to enhanced antigen presentation, the release of pro-inflammatory proteins, and 除上述药物外，目前正在研究新的免疫检查点抑制剂，如贝沙利单抗（BEX）。这种药物以清道夫受体 Clever1 为靶点，导致抗原呈递增强、促炎症蛋白释放和免疫抑制。
T-cell activation, showing promising results in solid tumor treatment [151]. Clever-1 is overexpressed on leukemic blasts and monocytes in patients with AML/MDS. In AML, BEX, as a single-agent therapy or in combination with azacitidine/venetoclax, enhances antigen presentation and activates T cells. In a phase- 1 trial that enrolled 22 MDS/AML subjects who were refractory to hypomethylating agents, the BEX-azacitidine combination was well tolerated and demonstrated efficacy across various indications [152]. 在实体瘤治疗中显示出良好的效果 [151]。在急性髓细胞性白血病/骨髓增生异常综合症患者中，Clever-1 在白血病囊泡和单核细胞上过度表达。在急性髓细胞性白血病中，BEX 作为一种单药疗法或与阿扎胞苷/韦尼妥类药物联合使用，可增强抗原呈递并激活 T 细胞。在一项招募了 22 名对低甲基化药物难治的 MDS/AML 受试者的 1 期试验中，BEX-阿扎胞苷联合疗法的耐受性良好，在各种适应症中均显示出疗效 [152]。
Recent studies suggest that in AML, macrophages might harbor leukemic mutations, which could affect their function and could represent potential therapeutic targets [153]. Thiostrepton, an antibiotic with antitumor effects on both hematological and non-hematological malignancies by targeting the PBX1-FOXM1 axis, was also found to modulate macrophage polarization [154-156]. Ex vivo experiments proved that thiostrepton induces apoptosis in the leukemic blast population and in the tumor-supportive macrophagemonocytic population in a dose-dependent manner [156]. Thiostrepton targets M1 and M2 macrophages; however, patients with high levels of M2 macrophages tend to benefit the most [156]. 最近的研究表明，在急性髓细胞性白血病中，巨噬细胞可能携带白血病突变，这可能会影响其功能，并可能成为潜在的治疗靶点 [153]。硫司他镑是一种抗生素，通过靶向 PBX1-FOXM1 轴对血液和非血液恶性肿瘤均有抗肿瘤作用，研究还发现它能调节巨噬细胞的极化[154-156]。体内外实验证明，硫司他镑能以剂量依赖的方式诱导白血病暴发性细胞群和肿瘤支持性巨噬单核细胞群凋亡[156]。硫司群肽可靶向 M1 和 M2 巨噬细胞，但 M2 巨噬细胞水平高的患者往往获益最多 [156]。
Rather than using macrophages as direct therapeutic targets, modulating their polarization yields promising results in cancer treatment and AML comprised. Macrophage receptors with a collagenous structure (MARCOs) are scavenger receptors that are highly expressed on TAMs and have been associated with a poor prognosis [157]. Eisinger and his colleagues altered macrophage polarization through anti-MACRO therapy, with the enhancement of NK-cell-dependent apoptosis [158]. In AML, high MACRO expression was linked to a high presence of M2 macrophages, suggesting that AML could benefit from anti-MACRO therapy [112]. 在癌症治疗和急性髓细胞性白血病的治疗中，与其将巨噬细胞作为直接治疗靶点，不如调节其极化，从而取得良好效果。具有胶原结构的巨噬细胞受体（MARCOs）是TAMs上高表达的清道夫受体，与不良预后有关[157]。Eisinger 及其同事通过抗 MACRO 治疗改变了巨噬细胞的极化，增强了 NK 细胞依赖性凋亡 [158]。在急性髓细胞性白血病中，MACRO的高表达与M2巨噬细胞的大量存在有关，这表明急性髓细胞性白血病可从抗MACRO治疗中获益[112]。
TLRs activate innate immunity and polarize macrophages towards the M1 phenotype during pathogen invasion. In a phase-two clinical trial, Brenda J. Weigel et al. used TLR7 agonists to activate innate immune responses in patients with relapsed/refractory malignant hemopathies, including six with AML. However, the results were not spectacular, as most patients had progressive disease, while only one patient obtained a partial response, and one was considered as having stable disease [159]. Nonetheless, further research involving larger groups of patients is necessary to examine the impact of TLR agonists in AML. TLRs 可激活先天性免疫，并在病原体入侵时将巨噬细胞极化为 M1 表型。在一项第二阶段临床试验中，Brenda J. Weigel 等人使用 TLR7 激动剂激活复发/难治性恶性血液病患者的先天性免疫反应，其中包括 6 名急性髓细胞白血病患者。然而，结果并不理想，因为大多数患者的病情都在进展，只有一名患者获得了部分应答，还有一名患者被认为病情稳定[159]。尽管如此，仍有必要对更多患者进行进一步研究，以探讨 TLR 激动剂对急性髓细胞性白血病的影响。
Macrophage migration inhibitory factor (MIF) is an inflammatory protein, highly expressed in AML blasts and in the sera of AML patients [160-163]. Administered as single agents in AML, MIF inhibitors reprogram macrophages to switch their phenotype towards M1, and even more so in association with pro-inflammatory cytokines and CSF1R inhibitors [164]. Spertini et al. combined granulocyte-macrophage colony-stimulating factor (GM-CSF) with MIF inhibitors and observed a transition of M2 macrophages towards the M1 phenotype, leading to enhanced apoptosis and reversal of resistance to FLT3 and BCL-2 targeted therapies. Furthermore, the association of MIF inhibitors and GM-CSF in xenograft models results in a leukemia burden decrease [165]. No clinical trials are available for this therapy as of yet, but the results seem promising. 巨噬细胞迁移抑制因子（MIF）是一种炎症蛋白，在急性髓细胞白血病细胞和急性髓细胞白血病患者的血清中高度表达 [160-163]。在急性髓细胞性白血病的单药治疗中，MIF 抑制剂可重塑巨噬细胞，使其表型转向 M1，与促炎细胞因子和 CSF1R 抑制剂联合使用时效果更佳 [164]。Spertini 等人将粒细胞-巨噬细胞集落刺激因子（GM-CSF）与 MIF 抑制剂结合使用，观察到 M2 巨噬细胞向 M1 表型转变，导致细胞凋亡增强，并逆转了对 FLT3 和 BCL-2 靶向疗法的耐药性。此外，在异种移植模型中联合使用 MIF 抑制剂和 GM-CSF 还能减少白血病负担 [165]。这种疗法目前还没有临床试验，但结果似乎很有希望。
7. Conclusions 7.结论
Due to their involvement in cancer progression and remarkable adaptability, targeting macrophages offers promising therapeutic options for neoplastic disease, hematological malignancies included. A more comprehensive understanding and characterization of macrophages associated with AML, both phenotypically and functionally, will aid in creating macrophage-targeted therapies that are more effective and less toxic. Future molecular strategies hold promise, such as monoclonal antibodies designed to modulate and enhance macrophage effectiveness against AML cells. The most promising approach to date focuses on the development of agents that target CD47 and CSF1R inhibitors. As of yet, despite some initial encouraging outcomes, infection and other potentially fatal complications outweigh the benefits. While the unfruitful results with magrolimab and pexidartinib may seem discouraging, new macrophage-targeting therapies are being explored and show 由于巨噬细胞参与癌症进展并具有显著的适应性，以巨噬细胞为靶点为肿瘤疾病（包括血液恶性肿瘤）提供了前景广阔的治疗方案。从表型和功能两方面更全面地了解和描述与急性髓细胞性白血病相关的巨噬细胞，将有助于开发更有效、毒性更低的巨噬细胞靶向疗法。未来的分子策略大有可为，例如设计单克隆抗体来调节和增强巨噬细胞对急性髓细胞白血病细胞的作用。迄今为止，最有希望的方法是开发针对 CD47 和 CSF1R 抑制剂的药物。到目前为止，尽管取得了一些令人鼓舞的初步成果，但感染和其他可能致命的并发症仍是得不偿失。尽管马格列单抗和pexidartinib的疗效不佳似乎令人沮丧，但新的巨噬细胞靶向疗法仍在探索之中，并显示出以下趋势
promising results with potentially improved safety profiles. Furthermore, reprogramming macrophage polarization towards the pro-inflammatory subtype using MACRO and MIF inhibitors was associated with lower resistance to therapy. This suggests the potential benefit of creating synergies between existing treatments and macrophage reprogramming agents. 结果很有希望，安全性也可能得到改善。此外，使用MACRO和MIF抑制剂将巨噬细胞极化重编程为促炎亚型与降低耐药性有关。这表明，在现有疗法和巨噬细胞重编程药物之间建立协同作用具有潜在的益处。
Author Contributions: Study conception and design: O.M., M.O., E.M., C.J., L.J., A.N., O.S., M.Z. and A.M.N.; Literature review: O.M., M.O., E.M., C.J., L.J., A.N., O.S., M.Z. and A.M.N.; Draft manuscript preparation: O.M., M.O., E.M., C.J., L.J., A.N., O.S., M.Z. and A.M.N.; Tables and Figures design: A.M.N. and O.M.; Coordination of authors: M.Z. and A.M.N. All authors have read and agreed to the published version of the manuscript. 作者贡献：研究构思和设计：O.M.、M.O.、E.M.、C.J.、L.J.、A.N.、O.S.、M.Z.和A.M.N.；文献综述：O.M.、M.O.、E.M.、C.J.、L.J.、A.N.、O.S.、M.Z.和 A.M.N.；草稿编写：O.M.、M.O.、E.M.、C.J.、L.J.、A.N.、O.S.、M.Z. 和 A.M.N.；表格和图表设计：A.M.N. 和 O.M.；作者协调：所有作者均已阅读并同意手稿的出版版本。
Funding: This research received no external funding. 资助：本研究未获得外部资助。
Institutional Review Board Statement: Not applicable. 机构审查委员会声明：不适用。
Informed Consent Statement: Not applicable. 知情同意声明：不适用。
Conflicts of Interest: The authors declare no conflict of interest. 利益冲突：作者声明无利益冲突。
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