更新于：2024-11-01

SDF-1

更新于：2024-11-01

基本信息

别名

趋化细胞因子CXCL12、C-X-C motif chemokine 12、C-X-C motif chemokine ligand 12

+ [21]

简介

Chemoattractant active on T-lymphocytes and monocytes but not neutrophils. Activates the C-X-C chemokine receptor CXCR4 to induce a rapid and transient rise in the level of intracellular calcium ions and chemotaxis. SDF-1-beta(3-72) and SDF-1-alpha(3-67) show a reduced chemotactic activity. Binding to cell surface proteoglycans seems to inhibit formation of SDF-1-alpha(3-67) and thus to preserve activity on local sites. Also binds to atypical chemokine receptor ACKR3, which activates the beta-arrestin pathway and acts as a scavenger receptor for SDF-1. Binds to the allosteric site (site 2) of integrins and activates integrins ITGAV:ITGB3, ITGA4:ITGB1 and ITGA5:ITGB1 in a CXCR4-independent manner (PubMed:29301984). Acts as a positive regulator of monocyte migration and a negative regulator of monocyte adhesion via the LYN kinase. Stimulates migration of monocytes and T-lymphocytes through its receptors, CXCR4 and ACKR3, and decreases monocyte adherence to surfaces coated with ICAM-1, a ligand for beta-2 integrins. SDF1A/CXCR4 signaling axis inhibits beta-2 integrin LFA-1 mediated adhesion of monocytes to ICAM-1 through LYN kinase. Inhibits CXCR4-mediated infection by T-cell line-adapted HIV-1. Plays a protective role after myocardial infarction. Induces down-regulation and internalization of ACKR3 expressed in various cells. Has several critical functions during embryonic development; required for B-cell lymphopoiesis, myelopoiesis in bone marrow and heart ventricular septum formation. Stimulates the proliferation of bone marrow-derived B-cell progenitors in the presence of IL7 as well as growth of stromal cell-dependent pre-B-cells (By similarity).

关联

项与 SDF-1 相关的药物

Dociparstat sodium

靶点

CXCR4 x SDF-1

作用机制

CXCR4拮抗剂 [+1]

在研机构

CANTEX, Inc. [+1]

原研机构

Cantex Pharmaceuticals, Inc.

在研适应症

新型冠状病毒感染

非在研适应症

急性肺损伤 [+8]

最高研发阶段临床3期

首次获批国家/地区-

首次获批日期1800-01-20

JVS-100

靶点

SDF-1

作用机制

SDF-1调节剂 [+4]

在研机构

SironRX Therapeutics, Inc. [+3]

原研机构

The Cleveland Clinic Foundation

在研适应症

心脏衰竭 [+3]

非在研适应症

心绞痛 [+6]

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

Emilimogene sigulactibac

靶点

SDF-1

作用机制

SDF-1刺激剂 [+2]

在研机构

Ilya Pharma AB初创企业

原研机构

University of Uppsala

在研适应症

糖尿病足溃疡 [+2]

非在研适应症-

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

项与 SDF-1 相关的临床试验

NCT04901741 / Not yet recruiting临床2期

An Open-label Phase 2 Study of Olaptesed Pegol (NOX-A12) Combined With Pembrolizumab and Nanoliposomal Irinotecan/5-FU/Leucovorin or Gemcitabine/Nab-paclitaxel in Microsatellite-stable Metastatic Pancreatic Cancer Patients

The purpose of this study is to provide a go/no-go decision for a randomized expansion study by assessing the disease control rate (DCR) at 6 weeks for the combination of olaptesed pegol on top of pembrolizumab and (Arm 1) nanoliposomal irinotecan, 5-FU and leucovorin or (Arm 2) gemcitabine and nab-paclitaxel, to assess safety and tolerability and time-to-event endpoints.

开始日期2025-06-01

申办/合作机构

TME Pharma NV

[+1]

NCT05608187 / Recruiting临床2期

A Randomized, Double-Blind, Placebo-controlled, Parallel, Exploratory Phase 2a Study to Evaluate Safety and Biological Effect on Wound Healing of ILP100-Topical in Subjects With Diabetic Foot Ulcers

A randomized, double-blind, placebo-controlled, parallel, exploratory phase 2a study to evaluate safety and biologic efficacy on wound healing of ILP100-Topical in subjects with diabetic foot ulcers during 26 weeks with a 5-year long-term follow-up period. A total of 30 subjects will be randomized to low dose of ILP100-Topical (ILP100Lo), high dose of ILP100-Topical (ILP100Hi) or Placebo according to a 1:1:1 randomization schedule.
The study will consist of a 3-weeks Screening and Run-in Phase, followed by a 5-week Treatment Phase starting from Baseline and an Assessment Phase from Week 5 to Week 26. Thereafter, the subjects will be followed yearly during 5 years in a Long-Term Safety Follow-up Phase.

开始日期2022-09-26

申办/合作机构

Ilya Pharma AB初创企业

ChiCTR2200057015 / Suspended临床1期

A phase I single-center, randomized, opened, dose-escalation study to evaluate the tolerability, safety and preliminary efficacy of GP51801 injection in the treatment of medium-thick donor site wounds

开始日期2022-04-20

申办/合作机构

南京济群医药科技股份有限公司

100 项与 SDF-1 相关的临床结果

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100 项与 SDF-1 相关的转化医学

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0 项与 SDF-1 相关的专利（医药）

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10,362

项与 SDF-1 相关的文献（医药）

2025-05-01·Neural Regeneration Research

Induced neural stem cells regulate microglial activation through Akt-mediated upregulation of CXCR4 and Crry in a mouse model of closed head injury

Article

作者: Xu, Ruxiang ; Guo, Lili ; Gao, Mou ; Dong, Qin ; Yang, Zhijun ; Zou, Dan

JOURNAL/nrgr/04.03/01300535-202505000-00025/figure1/v/2024-07-28T173839Z/r/image-tiff Microglial activation that occurs rapidly after closed head injury may play important and complex roles in neuroinflammation-associated neuronal damage and repair. We previously reported that induced neural stem cells can modulate the behavior of activated microglia via CXCL12/CXCR4 signaling, influencing their activation such that they can promote neurological recovery. However, the mechanism of CXCR4 upregulation in induced neural stem cells remains unclear. In this study, we found that nuclear factor-κB activation induced by closed head injury mouse serum in microglia promoted CXCL12 and tumor necrosis factor-α expression but suppressed insulin-like growth factor-1 expression. However, recombinant complement receptor 2-conjugated Crry (CR2-Crry) reduced the effects of closed head injury mouse serum-induced nuclear factor-κB activation in microglia and the levels of activated microglia, CXCL12, and tumor necrosis factor-α. Additionally, we observed that, in response to stimulation (including stimulation by CXCL12 secreted by activated microglia), CXCR4 and Crry levels can be upregulated in induced neural stem cells via the interplay among CXCL12/CXCR4, Crry, and Akt signaling to modulate microglial activation. In agreement with these in vitro experimental results, we found that Akt activation enhanced the immunoregulatory effects of induced neural stem cell grafts on microglial activation, leading to the promotion of neurological recovery via insulin-like growth factor-1 secretion and the neuroprotective effects of induced neural stem cell grafts through CXCR4 and Crry upregulation in the injured cortices of closed head injury mice. Notably, these beneficial effects of Akt activation in induced neural stem cells were positively correlated with the therapeutic effects of induced neural stem cells on neuronal injury, cerebral edema, and neurological disorders post–closed head injury. In conclusion, our findings reveal that Akt activation may enhance the immunoregulatory effects of induced neural stem cells on microglial activation via upregulation of CXCR4 and Crry, thereby promoting induced neural stem cell–mediated improvement of neuronal injury, cerebral edema, and neurological disorders following closed head injury.

2025-01-01·Chemico-Biological Interactions

Benzo(a)pyrene promotes autophagy to impair endometrial decidualization via inhibiting CXCL12/CXCR4 axis

Article

作者: Liu, Taihang ; Liu, Fengxia ; Huang, Jiaying ; Xie, Hongye ; Li, Fangfang ; Ruan, Lingyan ; Gao, Rufei ; He, Junlin ; Chen, Xuemei ; Qi, Tao ; Xu, Hanting

Benzo(a)pyrene (BaP), a pervasive environmental pollutant with endocrine-disrupting properties, has been associated with detrimental effects on pregnancy. During early pregnancy, the endometrial decidualization process is critical for embryo implantation. Abnormal decidualization can lead to implantation failure, aberrant placental formation, and pregnancy loss. We previously revealed that BaP exposure impaired decidualization and implantation in mice, yet the underlying mechanisms remained elusive. Autophagy, a cellular mechanism pivotal for energy and material recycling, contributes to the decidualization process. The chemokine C-X-C motif chemokine ligand 12 (CXCL12), secreted by endometrium stromal cells (ESCs), is involved in regulating endometrial decidualization and autophagy. Therefore, this study aimed to explore the hypothesis that BaP disrupts the decidualization process by interfering with autophagic pathways via the CXCL12/CXCR4 axis during early pregnancy. We found that BaP inhibited CXCL12/CXCR4 expression, and induced autophagy by promoting autophagosome formation, which in turn impaired the decidualization in early pregnant mice uterus and decidual stromal cells (DSCs). Using autophagy inhibitors 3-methyladenine and chloroquine in combination with BaP to treat DSCs, successfully weakened BaP-induced autophagy, and relieved decidual injury. Additionally, activation of CXCL12/CXCR4 by recombinant protein CXCL12 attenuated BaP-induced autophagy, inhibited the PI3K/AKT signal activation caused by BaP, and partly rescued the expression of decidualization-related genes. In summary, this study demonstrates that BaP induces autophagy in DSCs by inhibiting the CXCL12/CXCR4 axis, leading to damage in endometrial decidualization during early pregnancy. The findings provide a critical chemokine-mediated regulatory mechanism involved in embryo implantation and contribute valuable knowledge to the reproductive toxicology of BaP.

2025-01-01·International Journal of Cardiology

Effect of tocilizumab on endothelial and platelet-derived CXC-chemokines and their association with inflammation and myocardial injury in STEMI patients undergoing primary PCI

Article

作者: Dahl, Tuva B ; Dahl, Tuva B. ; Seljeflot, Ingebjørg ; Kleveland, Ola ; Broch, Kaspar ; Wiseth, Rune ; Anstensrud, Anne Kristine ; Huse, Camilla ; Gullestad, Lars ; Ueland, Thor ; Halvorsen, Bente ; Aukrust, Pål ; Andersen, Geir Øystein ; Tøllefsen, Ingvild Maria ; Damås, Jan Kristian ; Woxholt, Sindre

BACKGROUNDTocilizumab improves myocardial salvage in ST-elevation myocardial infarction (STEMI) patients when administered before percutaneous coronary intervention (PCI). The mechanisms underlying ischemia-reperfusion injury remain unclear. In this sub-study, we investigated whether endothelial and platelet-derived CXC chemokines are involved, as they represent inflammatory mediators from two cell types relevant to myocardial infarction. Associations between these chemokines and neutrophils, C-reactive protein (CRP), troponin T (TnT), myocardial salvage index (MSI), microvascular obstruction (MVO), and infarct size.METHODSThis is a sub-study of the ASSAIL-MI trial, a double-blind clinical trial that randomized 199 STEMI patients to receive either 280 mg tocilizumab (n = 101) or placebo (n = 98) intravenously before PCI. Blood samples were collected prior to infusion, at day 1-2, 3-7, and at 3 and 6 months. Heparin was administered before baseline in 150 patients, while 49 received it after. We measured CXC-chemokines CXCL4, CXCL5, CXCL6, CXCL7, and CXCL12 using immunoassays. Cardiac MRI was performed in the first week and at 6 months.RESULTSTocilizumab did not significantly affect CXC-chemokines levels. Although some correlations were observed between chemokine levels and neutrophil counts and CRP, none of the CXC chemokines were associated with infarct size, MSI, MVO, or TnT levels. Notably, CXCL 12 levels increased in patients who received heparin before baseline, while other CXC-chemokines decreased significantly.CONCLUSIONThis study suggests that the beneficial effects of tocilizumab in STEMI patients are not due to changes in circulating endothelial or platelet-derived CXC-chemokines, compared to placebo. However, heparin significantly influences the levels of these chemokines.

118

项与 SDF-1 相关的新闻（医药）

2024-10-24

·生物探索

Nat Immunol丨年龄相关的上皮细胞缺陷限制胸腺的功能和再生

引言随着年龄的增长，胸腺会经历退化，导致组织萎缩、基质结构破坏、新生T细胞输出减少，最终对新抗原的响应能力下降【1】。胸腺对急性损伤（如压力、感染或癌症治疗）非常敏感，这些损伤会导致胸腺功能受损。尽管胸腺具有强大的再生能力，但这种能力随着年龄的增长而下降【2】。胸腺损伤后，胸腺的再生能力随着年龄的增长而下降，导致T细胞数量减少，这是移植相关发病率和死亡率的重要原因。最近的研究表明，胸腺上皮细胞 (TEC) 在年轻和老年小鼠以及人类中表现出显著的异质性【3-4】。但TEC 如何协调T细胞分化以及这些过程中的功能障碍如何与自身免疫和免疫缺陷相关目前尚不清楚。此外，目前关于胸腺萎缩和再生后损伤的机制仍然知之甚少。近日，来自美国纪念斯隆-凯特琳癌症中心的Marcel R. M. van den Brink研究团队、弗雷德·哈钦森癌症研究中心的Jarrod A. Dudakov研究团队以及沃尔特和伊丽莎·霍尔医学研究所的Daniel H. D. Gray研究团队合作在Nature Immunology杂志上发表题为Age-related epithelial defects limit thymic function and regeneration的研究论文，该研究项利用单细胞和空间转录组学、谱系追踪和高级成像技术，研究胸腺基质细胞中与年龄相关的变化，并确定胸腺萎缩和再生能力下降的潜在机制。研究人员利用多种先进的实验技术，包括单细胞测序、空间转录组学、谱系追踪和高级成像，发现并定义了两种年龄相关的胸腺上皮细胞aaTECs（aaTEC1和aaTEC2）。这些细胞形成高密度的上皮细胞簇，缺乏胸腺细胞，表现出上皮-间质转化（EMT）的特征，并下调 FOXN1 表达。谱系追踪研究表明，aaTECs来自FOXN1阳性的上皮细胞。FOXN1是胸腺上皮谱系的关键调节因子，参与TEC的分化和功能维持。FOXN1表达的减少导致TEC向aaTECs分化，从而影响胸腺功能。接着研究人员探索aaTECs与胸腺功能的关系。研究发现aaTECs吸收其他TECs的生长信号，包括成纤维细胞分泌的成纤维细胞生长因子（FGF）和骨形态发生蛋白（BMP）。这些生长信号对于TEC的增殖和分化至关重要，而aaTECs的出现导致这些信号无法到达其他TECs，从而抑制了胸腺细胞的发育和成熟。此外，aaTECs形成不支持胸腺细胞发育的微环境。它们缺乏表达重要的胸腺细胞发育因子，如DLL4、Psmb11、Kitl、Ccl25、Cxcl12和 Il7。这些因子对于胸腺细胞的增殖、分化和选择至关重要。因此，aaTECs的存在导致胸腺细胞发育停滞，进一步导致胸腺功能下降。胸腺对急性损伤非常敏感，例如辐射和化疗。然而，胸腺也具有强大的再生能力。研究发现，急性损伤后，aaTECs会进一步扩张，这可能与胸腺再生途径的紊乱有关。aaTECs的扩张导致胸腺萎缩的修复缺陷，从而影响T细胞的重建和免疫功能。除了 TECs 之外，胸腺衰老还涉及其他细胞类型的变化。研究发现，衰老导致间充质谱系细胞（如成纤维细胞）的增多，以及纤维母细胞中炎症老化程序的上调。这些变化可能也与 aaTECs的出现有关。总之，该研究揭示了胸腺衰老的复杂机制，发现aaTECs的出现是导致胸腺功能下降和再生能力受损的关键因素。这些发现为开发改善老年人免疫功能的疗法提供了新的思路，并为深入理解胸腺衰老的机制奠定了基础。参考文献 1. Granadier, D., Iovino, L., Kinsella, S. & Dudakov, J. A. Dynamics of thymus function and T cell receptor repertoire breadth in health and disease. Semin. Immunopathol. 43, 119–134 (2021). 2. Velardi, E., Tsai, J. J. & van den Brink, M. R. M. T cell regeneration after immunological injury. Nat. Rev. Immunol. 21, 277–291 (2021). 3. Baran-Gale, J. et al. Ageing compromises mouse thymus function and remodels epithelial cell differentiation. eLife (2020). 4. Dhalla, F. et al. Biologically indeterminate yet ordered promiscuous gene expression in single medullary thymic epithelial cells. EMBO J. (2019). https://www-nature-com.libproxy1.nus.edu.sg/articles/s41590-024-01915-9 责编|探索君排版|探索君来源|BioArt End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

AACR会议临床结果

2024-09-20

·医药观澜

誉衡生物CXCR4拮抗剂癌症新药在中国澳门获批上市

▎药明康德内容团队报道今日（9月20日），誉衡生物宣布靶向趋化因子受体4（CXCR4）的多肽类药物莫替福肽（APHEXDA®，motixafortide）近日获得中国澳门特别行政区药物监督管理局正式批准上市。该产品用于在多发性骨髓瘤（MM）患者中联合粒细胞集落刺激因子（G-CSF）动员造血干细胞，用于外周血的干细胞单采及随后的自体移植。莫替福肽已于2023年9月获美国FDA批准上市，为一款用于MM患者的创新干细胞动员剂。在骨髓微环境中，CXCR4与基质细胞衍生因子1（SDF-1/CXCL12）在造血干细胞归巢和驻留、调节免疫细胞分布的过程中起重要作用，造血干细胞通过CXCR4与SDF-1/CXCL12相互作用被锚定在骨髓基质内。莫替福肽是一款皮下注射的CXCR4拮抗剂，具有高亲合力的创新环肽结构，受体占有时间超过72小时，并有延长的体内活性。莫替福肽通过6个位点与干细胞表面CXCR4受体结合，精准阻断CXCR4与SDF-/CXCL12的相互作用，使得干细胞失锚定从骨髓中释放并迁移到外周血中，从而显著提高CD34+细胞采集量，缩短采集次数，增加移植成功率。同时调节免疫细胞的迁移与活化，影响机体的免疫反应。根据誉衡生物新闻稿介绍，莫替福肽的批准是基于GENESIS全球多中心3期注册研究的结果，该研究旨在比较莫替福肽+G-CSF与安慰剂+G-CSF在自体干细胞移植（ASCT）前接受造血干细胞动员的MM患者中的安全性和有效性。这项随机、双盲、安慰剂对照研究均达到了所有主要和关键次要终点，安全性良好且耐受。研究结果已于《自然-医学》（Nature Medicine）杂志发表。这项临床研究显示，在莫替福肽+G-CSF可高效动员干细胞。仅一次用药，88.8%的患者通过一次单采、92.5%的患者最多通过两次单采即可获得理想剂量6×106/公斤体重CD34+细胞；接受安慰剂+G-CSF的患者中比例分别为9.5%和26.2%。莫替福肽显著提高了造血干细胞的采集效率和质量，为移植成功奠定基础。此外，数据还表明，莫替福肽诱导了多种造血干细胞和祖细胞（HSPC）亚群的全动员，这些亚群能够进行广泛的多谱系造血重建。另一项研究也显示莫替福肽无论是单独使用还与G-CSF联合使用，其疗效都明显优于小分子CXCR4阻断剂，可快速动员细胞（中性粒细胞、单核细胞和造血祖细胞）进入外周血，并且在注射后24小时内仍保持较高的动员水平。基于莫替福肽的生物学机制以及广泛的临床前及临床探索，该药物还具有更广的应用潜力，例如在肿瘤免疫治疗和放化疗中展现出显著的增效减毒作用，也可以增强感染高风险和免疫力低下人群的免疫力。基于莫替福肽的作用机制特点和已有的临床数据，誉衡生物计划在实体肿瘤及细胞治疗中开发其他潜在适应症，包括与全人源PD-1单抗赛帕利单抗联合用药治疗一线胰腺癌。此前一项莫替福肽与PD-1抑制剂及标准化疗联合用药治疗一线胰腺癌的二期临床研究（CheMo4METPANC）在2023年AACR会议上发布。研究显示探索性阶段入组的11例患者，总体应答率（ORR）为64%；无进展生存期中位数（mPFS）为9.6个月，疾病控制率（DCR）为82%。其它潜在适应症包括细胞治疗中的CD34+细胞动员、改善化疗药物的骨髓抑制、升白、免疫修复等。参考资料： [1] 誉衡生物宣布莫替福肽（APHEXDA®，motixafortide）获中国澳门药物监督管理局批准上市.Retrieved Sep 20，2024, from https://mp.weixin.qq.com/s/FsUpkYKIti9ilEMY75XNMw 本文由药明康德内容团队根据公开资料整理编辑，欢迎个人转发至朋友圈。转发授权或其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

上市批准临床3期临床结果

2024-09-06

·奇点网

竟是来自肺部原住民的深情呼唤。

*仅供医学专业人士阅读参考肿瘤转移是癌症患者的主要死亡原因。许多实体瘤在挑选新的家园进行转移时，往往倾向于选择特定器官作为转移目标，即所谓的器官特异性转移，比如肺部是乳腺癌最常见的转移目标之一。逃离的乳腺癌细胞究竟看上了肺部哪一点，如此钟情于移民到肺部？重庆医科大学柳满然团队的最新研究给出了答案，原来是有肺部原住民在夹道欢迎乳腺癌细胞。论文于近日发表在《癌症通讯》期刊上。他们在肺部微环境中鉴定了三种与肿瘤相关的成纤维细胞亚型，发现它们的表达特征随着肺转移的进展而变化。其中，表达TDO2的基质成纤维细胞（MFs）在调控乳腺癌肺转移过程中起着关键作用，能够通过产生犬尿氨酸帮助游离肿瘤细胞（DTCs）抵抗铁死亡，并引起T细胞功能障碍，从而促进肿瘤细胞的生存和免疫逃逸。通过靶向这些细胞可以显著减少肺转移和改善免疫反应。论文截图成纤维细胞是肺微环境中的主要细胞。在这项研究中，柳满然团队首先利用小鼠实验发现，随着乳腺癌向肺部转移的进展，肺部的成纤维细胞逐渐获得促进转移的特性，且伴随着细胞外基质的重塑，这是肿瘤转移微环境的标志性特征。接下来，研究团队使用单细胞RNA测序分析识别了三种肺成纤维细胞亚型，分别为基质成纤维细胞（MFs）、肌成纤维细胞1型（MyoF1）、肌成纤维细胞2型（MyoF2）。MFs主要表达与细胞外基质相关的基因，如胶原蛋白、纤维连接蛋白、硫酸软骨素蛋白多糖，以及高表达Cxcl12、Il6、C3等多种炎症趋化因子和补体基因，提示MFs可能在免疫调节中发挥作用；MyoF1和MyoF2主要表达与肌肉收缩和血管生成相关的基因。鉴定了3种肺成纤维细胞亚型他们还观察到，在不同的乳腺癌转移阶段，成纤维细胞亚型的组成发生着动态重塑。MFs在乳腺癌的所有阶段中占据主导地位，MyoF1的占比在肺部形成初级微小转移灶的阶段逐渐增加，MyoF2的占比在转移发生前逐渐增加并在后续阶段减少。很明显，肺部成纤维细胞参与了乳腺癌转移。但摆在面前的有三种成纤维细胞亚型，究竟是谁在为游离的乳腺癌细胞狠狠卖命，还需要继续追责。研究团队通过流式细胞术去除了免疫细胞的干扰，以便更好地捕捉肺部转移灶中游离肿瘤细胞与肺部微环境细胞之间的相互作用。分析结果显示，MFs是与肿瘤细胞相互作用最密切的细胞类型，且MFs水平高与乳腺癌患者肺转移后的生存率降低密切相关。使用条件性敲除小鼠模型选择性消耗MFs，可以观察到这些小鼠的肺部转移负担显著减少，生存期显著延长，表明MFs在促进转移形成中起关键作用。MFs与乳腺癌肺转移患者生存相关进一步研究表明，乳腺癌肺转移微环境中，相较于其他两种类型肺成纤维细胞，色氨酸2,3-双加氧酶（TDO2）仅在MFs中特异性高表达，且TDO2催化色氨酸代谢生成犬尿氨酸（KYN）的过程在MFs中高度活跃。研究团队发现，MFs利用TDO2为乳腺癌的肺转移完成了里呼外应。一方面，高表达TDO2的MFs将犬尿氨酸分泌到肺转移微环境中，可以上调DTC中铁死亡调控因子FTH1的表达，降低DTC细胞内二价铁离子的积累，从而增强游离肿瘤细胞对铁死亡的抵抗；另一方面，MFs分泌的犬尿氨酸还能够作用于浸润T细胞，促进T细胞功能障碍，并阻止T细胞进入转移灶，形成了免疫抑制的“冷肿瘤”微环境，帮助DTCs逃避免疫系统攻击。机制使用TDO2抑制剂（680C91）或者敲除基因表达，可以显著减少游离肿瘤细胞对铁死亡的抗性，部分恢复T细胞的杀伤能力和减少肿瘤的免疫逃逸，并降低乳腺癌小鼠的肺部转移负担。但是乳腺癌小鼠的肝脏、骨和脑转移负担没有显著变化，表明MFs-TDO2信号通路介导的促肿瘤转移作用在肺部具有特异性。在乳腺癌患者中，肺部表达较高水平的TDO2与肺转移风险增加及预后恶化有关。这项研究描绘了乳腺癌肺转移微环境中的成纤维细胞亚型，揭示MFs及其表达的TDO2是肺部“吸引”游离乳腺癌细胞的罪魁祸首，或成为针对性治疗乳腺癌肺转移的有效靶点。参考文献：[1]https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/10.1002/cac2.12608本文作者丨张艾迪