Nature重磅技术TransTAC选中的受体！TFR1这个铁转运蛋白要火了

转铁蛋白受体1（TFR1/CD71/TFRC）是细胞表面负责铁离子摄取的跨膜糖蛋白，在细胞增殖和代谢中发挥关键作用。TFR1在多数实体瘤中高表达，且与肿瘤进展和免疫微环境密切相关。近年来，TFR1研究已从经典铁代谢拓展至肿瘤靶向治疗、铁死亡调控和免疫逃逸等前沿领域。2025年《Cancers》研究揭示TFR1高表达与免疫浸润微环境和免疫检查点分子上调相关，提示其可作为免疫治疗敏感性预测标志物；同年CD24-H7双特异性降解剂通过招募TFR1实现CD24溶酶体降解，增强抗肿瘤免疫；CD36-p38-CEBPB-TfR1轴被证实驱动肝癌CD8+ T细胞铁蓄积和功能障碍。此外，TFR1在胶质母细胞瘤和膀胱癌中与铁死亡敏感性密切相关。这些进展表明TFR1在肿瘤靶向治疗、免疫调控和铁死亡领域具有重要转化价值。

1. 什么是TFR1？ 1.1 TFR1的结构 

转铁蛋白受体1（Transferrin receptor protein 1，TFR1）也被称为CD71或TFRC。TFR1/TFRC是一种II型跨膜蛋白，是调节细胞内铁元素转运过程的最重要膜蛋白。TFR1是由两个同源二聚体的亚基通过二硫键交联而成。每个单体包含一个大的胞外C端区域，一个单跨膜区域及一个短的N端区域。C端区域作为外功能区，包含了与转铁蛋白（Transferrin，Tf）相结合的位点（图1） ^[2-4]。目前已发现两种转铁蛋白受体，分别是TFR1和TFR2，它们在结构和功能上都比较相似。在正常生理条件下，TFR1与转铁蛋白Tf发生相互作用，促进铁的吸收。这种结合形式是血液中铁的主要存在方式 ^[5-6]。

图1. TFR1的结构 ^[2]

1.2 TFR1的表达 

TFR1是一种广泛表达于人体几乎所有细胞和组织类型中的膜蛋白。TFR1在人体需要铁元素时发挥作用，介导铁离子的转运和代谢。TFR1的表达广泛分布于免疫系统、造血系统（如骨髓干细胞、红细胞和白细胞）、神经系统（如神经元和神经胶质细胞）、生殖系统、心脏、肝脏、肾脏等各种组织和细胞类型。TFR1的表达水平受多种因素影响，包括细胞内铁含量、细胞分化状态、激素调节以及炎症状态等 ^[7-9]。

1.3 TFR1的功能 

TFR1最主要的生理功能是与转铁蛋白（transferrin，Tf）结合，通过内吞方式介导细胞对铁的摄取。因此，Tf-TFR1系统被认为是机体获取铁离子的重要途径。具体而言，首先，Tf和铁离子（Fe³⁺或Fe²⁺形式）结合后，其空间结构随之发生相应变化，将铁离子包入蛋白内形成Tf-Fe²⁺。其次，TFR1在生理pH下与Tf-Fe²⁺结合，Tf-TFR1复合物被网格蛋白（Clathrin）通过小窝的内吞作用内部化（图2） ^[10-12]。

随之，胞内Tf-TFR1复合物被运输至内体酸化，TFR1和Tf的氨基酸残基相互作用，引起构象改变促使铁离子释放，TFR1通过高尔基复合体循环至细胞表面完成铁离子运输。总之，TFR1在细胞和组织中扮演着重要角色，通过TFR1的调节来平衡细胞内铁含量，维持人体铁稳态是保证人体各项生理机能正常运作的必要条件 ^[10-12]。

图2. Tf-TFR1系统平衡细胞内铁含量 ^[2]

2. TFR1相关的调控机制 

TFR1是细胞最重要的铁元素摄取因子。TFR1表达量下降或异常会导致细胞缺铁，而过多的铁则可能催化活性氧（ROSs）并损伤生物大分子。为了确保充足的铁元素同时避免其毒性，细胞已经发展出多种机制来调控TFR1表达水平。尽管TFR1异常表达在多种疾病中发挥作用，但其分子机制和作用仍未完全明确。因此，还需要更深入地研究和探索。

TFR1的表达受多种刺激条件调控。在转录水平中，当细胞发生缺氧时，缺氧诱导因子（HIF）和其他转录因子如c-Myc、GATA1、Ets-1以及促红细胞生成素Stat5可以促进其转录。TFR1的转录后水平主要由IRP1和IRP2调控，它们与TFR1 mRNA中的IRE结合来影响基因表达 ^[13-15]。

在翻译后水平，CD133（PROM1）是TFR1转运铁元素过程中的负调节因子，同时EGF受体、c-Abl分子和MARCH8分子可能也参与其中。如下图所示，一项研究揭示FLCN有可能在翻译、或者翻译后水平调控TFR1的表达，即Tf-TFR1复合物可与含有Rab11蛋白的循环内体相结合，回到细胞膜上（图3）^[13-17]。

TFR1在疾病中发挥调控作用。例如，在胶质瘤中，TFR1通过炎症反应，细胞周期，DNA损失及DNA甲基化等机制参与胶质瘤的发生发展。此外，PD1信号，如IL17，IL18，NF-kβ，FOXM1，FOCAL及JAK-STAT信号可能是TFR1调控的关键信号通路 ^[18-20]。在神经干细胞中敲除TFR1发现，条件性敲除小鼠有癫痫的症状。并且在此研究中还发现GluA2在海马神经元突触上表达增加，其中突触前的神经递质释放能力下降，突触后长时程增强（LTP）受到一定的抑制 ^[21-23]。

图3. FLCN通过Rab11A调控Tf-TFR1蛋白的回收运输 ^[17]

3. TFR1在肿瘤、神经退行性等疾病中的作用 

正常人体铁代谢处于平衡状态，当其中的某一调控环节出现异常导致平衡被打破时，会影响细胞内自由基形成并加速氧化应激反应进展，同时也可导致肿瘤发生和发展。TFR1作为细胞摄取铁元素过程中最重要的调控受体，在多种疾病的发生发展过程中起到重要作用。

3.1 TFR1和肿瘤 

现有研究表明TFR1在甲状腺癌 ^[24]、食管鳞状细胞癌 ^[25]、乳腺癌 ^[26]、肝癌 ^[27]、结肠癌 ^[28]、白血病 ^[29]、肺癌 ^[30]、胰腺癌 ^[31]、鼻咽癌 ^[31]等恶性肿瘤中显著表达。但在部分恶性肿瘤中，TFR1表达情况尚不明确，其中包括：前列腺癌、睾丸癌等。例如，在肝癌中，TFR1在肝癌中的表达与甲胎蛋白和血清凝血酶原的浓度有关 ^[27]；在乳腺癌中，敲降IRP2表达，可提高铁蛋白重链的表达，并下调TFR1蛋白表达，从而抑制乳腺癌细胞的生长 ^{[26, 32]}；在结肠癌中，TFR1的高表达可激活IL-6/IL-11-Stat3信号通路，促进结肠上皮细胞的增殖和凋亡，从而加重结肠黏膜的损伤并导致结肠癌的发生 ^{[28, 33]}。

3.2 TFR1和神经退行性疾病 

铁代谢的紊乱是引发神经退行性疾病的病理生理机制之一。铁在大脑中的蓄积，与阿尔茨海默病、帕金森病、肌萎缩侧索硬化等神经退行性疾病有关 ^[34]。阿尔茨海默病是最常见神经退行性疾病之一，其主要以淀粉样斑块的积聚以及某些神经元的丢失为发病特征。有研究表明，抑制阿尔兹海默模型小鼠大脑颞叶皮层中的铁摄取蛋白TFR1、TF以及DMT1的表达，可有效缓解铁过载状态 ^[35-36]。

3.3 TFR1和贫血 

TFR1与Tf复合物的结合，对红细胞生成过程中细胞获取铁元素有着重要意义。当人体内发生缺铁或者红细胞生成增多时，TFR1的表达将被反应性上调。临床研究证实，地中海贫血小鼠体内的溶性转铁蛋白受体（sTFR1）和TF的水平都显著高于正常值。进一步研究揭示，TFR1在β-地中海红系前体细胞中异常高表达，降低TFR1的表达可有效调节贫血小鼠中无效红细胞的生成并改善小鼠的贫血以及铁过载情况 ^{[7, 37]}。

3.4 TFR1和其它疾病 

TFR1不仅参与细胞铁离子运输，有研究提示TFR1还可作为多种病毒受体介导HCV与宿主细胞膜融合，在HCV入胞过程中发挥重要作用。丙型肝炎病毒（HCV）是导致慢性化肝炎、原发性肝癌的主要病原体。因此，TFR1作为HCV抗病毒靶点的潜在可能性值得关注 ^[38-40]。在神经元中，研究发现TFR1对mGlul的转运起到重要的调节作用，并且可能参与了mGlul信号通路，且对小脑的运动协调能力起到影响 ^[41-42]。

4. TFR1临床研究前景 

TFR1的临床转化呈现多元化格局。在ADC药物方面，CX-2029是首--个靶向CD71的Probody-药物偶联物（PDC），通过蛋白酶激活设计限制正常组织暴露，在I期临床试验中展现首--个人体抗肿瘤活性，目前持续临床评估中。在双特异性抗体方面，trontinemab（RO7126209）为抗Aβ/抗TfR1双抗，利用TFR1介导的跨血脑屏障转胞吞递送抗体至中枢，脑摄取提升4-18倍，已进入II期用于阿尔茨海默病。在蛋白降解领域，TransTAC技术利用TFR1循环内吞实现膜蛋白高效降解，已用于CAR-T活性调控；CD24-H7双特异性降解剂通过TFR1介导CD24溶酶体降解增强抗肿瘤免疫。在铁死亡治疗方面，TFR1高表达肿瘤对铁死亡诱导剂敏感性增强，青-蒿-素通过TFRC-HSPA9轴选择性诱导胃癌铁死亡。总体而言，TFR1在PDC、双抗、蛋白降解和铁死亡诱导等方向均展现临床转化前景，未来需在靶向特异性、安全性和联合免疫治疗策略方面深入探索。

5. 华美生物TFR1相关产品 

● TFR1重组蛋白

Recombinant Human Transferrin receptor protein 1(TFRC),partial (Active) (Code: CSB-MP3648HU)

Recombinant Cynomolgus monkey Transferrin receptor protein 1 (EGM_21146), partial (Active) (Code: CSB-MP5092MOV)

● TFR1抗体

● TFR1 ELISA试剂盒

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