Inhibiting cancer metastasis with water-solubilized membrane receptor CXCR4QTY-Fc as a molecular trap

IF 7.2 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology Pub Date : 2025-08-21 DOI:10.1016/j.chembiol.2025.07.006

Changfa Sun , Shilei Hao , Lili Wang , Run Meng , Hui Wang , Wenfeng Li , Jia Deng , Qiudan Yin , Xiaoliang Chen , Tingxiu Xiang , Zuojin Liu , Haiming Zheng , Zhongli Luo , Kaiyong Cai , Bochu Wang , Shuguang Zhang , Rui Qing

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Abstract

The CXCR4/CXCL12 axis is vital for tumor metastasis and immune evasion in various cancers. However, developing effective inhibitors is challenging due to complex intracellular interactions and limitations of soluble receptor drugs targeting single transmembrane proteins. Here, we engineered a water-soluble CXCR4^QTY-Fc molecular trap by fusing a redesigned CXCR4 variant with the IgG1-Fc domain. CXCR4^QTY-Fc effectively neutralizes CXCL12, inhibits CXCR4 downstream signaling, and suppresses migration and invasion of CXCR4-positive cancer cells in vitro, even with dipeptidyl peptidase 4 (DPP-4) inhibition. In mouse models of pancreatic, breast, and prostate cancer metastasis, CXCR4^QTY-Fc significantly reduced tumor metastasis, outperforming the clinical CXCR4 antagonist AMD3100. Mechanistically, CXCR4^QTY-Fc blocks endosomal CXCL12/CXCR4 signaling and reshapes the tumor microenvironment by downregulating CXCL12, thereby inhibiting tumor growth, metastasis, and angiogenesis. This biomimetic, non-immunogenic approach offers a promising strategy for broad-spectrum metastasis inhibition.

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水溶性膜受体CXCR4QTY-Fc作为分子陷阱抑制肿瘤转移

CXCR4/CXCL12轴在多种癌症的肿瘤转移和免疫逃避中至关重要。然而，由于复杂的细胞内相互作用和针对单一跨膜蛋白的可溶性受体药物的局限性，开发有效的抑制剂是具有挑战性的。在这里，我们通过将重新设计的CXCR4变体与IgG1-Fc结构域融合，设计了一个水溶性CXCR4QTY-Fc分子陷阱。CXCR4QTY-Fc在体外有效中和CXCL12，抑制CXCR4下游信号，抑制CXCR4阳性癌细胞的迁移和侵袭，甚至抑制二肽基肽酶4 （DPP-4）。在胰腺、乳腺和前列腺癌转移的小鼠模型中，CXCR4QTY-Fc显著降低肿瘤转移，优于临床CXCR4拮抗剂AMD3100。机制上，CXCR4QTY-Fc阻断内体CXCL12/CXCR4信号通路，通过下调CXCL12重塑肿瘤微环境，从而抑制肿瘤生长、转移和血管生成。这种仿生的、非免疫原性的方法为广谱转移抑制提供了一种很有前途的策略。

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来源期刊

Cell Chemical Biology Biochemistry, Genetics and Molecular Biology-Molecular Medicine

CiteScore

14.70

自引率

2.30%

发文量

143

期刊介绍： Cell Chemical Biology, a Cell Press journal established in 1994 as Chemistry & Biology, focuses on publishing crucial advances in chemical biology research with broad appeal to our diverse community, spanning basic scientists to clinicians. Pioneering investigations at the chemistry-biology interface, the journal fosters collaboration between these disciplines. We encourage submissions providing significant conceptual advancements of broad interest across chemical, biological, clinical, and related fields. Particularly sought are articles utilizing chemical tools to perturb, visualize, and measure biological systems, offering unique insights into molecular mechanisms, disease biology, and therapeutics.