Inhibiting cancer metastasis with water-solubilized membrane receptor CXCR4^QTY-Fc as a molecular trap

Changfa Sun¹, Shilei Hao², Lili Wang³, Run Meng³, Hui Wang⁴, Wenfeng Li³, Jia Deng⁵, Qiudan Yin³, Xiaoliang Chen⁶, Tingxiu Xiang⁷, Zuojin Liu⁸, Haiming Zheng⁹, Zhongli Luo¹⁰, Kaiyong Cai³, Bochu Wang¹¹, Shuguang Zhang¹², Rui Qing¹³

Affiliations

¹ Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China; State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
² Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China; Media Lab, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: shilei_hao@cqu.edu.cn.
³ Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China.
⁴ State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
⁵ College of Environment and Resources, Chongqing Technology and Business University, Chongqing 400067, China.
⁶ Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China; Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China.
⁷ Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China.
⁸ Hepatobiliary Surgery Department, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
⁹ Digestive Endoscopic Center, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
¹⁰ College of Basic Medical Sciences, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China.
¹¹ Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China. Electronic address: wangbc2000@126.com.
¹² Media Lab, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: shuguang@mit.edu.
¹³ State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China; Media Lab, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: ruiqing.br@sjtu.edu.cn.

PMID: 40845831
DOI: 10.1016/j.chembiol.2025.07.006

Inhibiting cancer metastasis with water-solubilized membrane receptor CXCR4^QTY-Fc as a molecular trap

Changfa Sun et al. Cell Chem Biol. 2025.

. 2025 Aug 21;32(8):1058-1074.e6.

doi: 10.1016/j.chembiol.2025.07.006.

Authors

Affiliations

¹ Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China; State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
² Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China; Media Lab, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: shilei_hao@cqu.edu.cn.
³ Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China.
⁴ State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
⁵ College of Environment and Resources, Chongqing Technology and Business University, Chongqing 400067, China.
⁶ Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China; Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China.
⁷ Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China.
⁸ Hepatobiliary Surgery Department, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
⁹ Digestive Endoscopic Center, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
¹⁰ College of Basic Medical Sciences, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China.
¹¹ Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China. Electronic address: wangbc2000@126.com.
¹² Media Lab, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: shuguang@mit.edu.
¹³ State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China; Media Lab, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: ruiqing.br@sjtu.edu.cn.

PMID: 40845831
DOI: 10.1016/j.chembiol.2025.07.006

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.

Keywords: CXCL12; CXCR4; QTY code; molecular traps; pancreatic cancer; tumor metastasis inhibition.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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Inhibiting cancer metastasis with water-solubilized membrane receptor CXCR4^QTY-Fc as a molecular trap

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Inhibiting cancer metastasis with water-solubilized membrane receptor CXCR4^QTY-Fc as a molecular trap

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