CDH17-targeting CAR-NK cells synergize with CD47 blockade for potent suppression of gastrointestinal cancers

Liuhai Zheng; Youbing Ding; Xiaolong Xu; Huifang Wang; Guangwei Shi; Yang Li; Yuanqiao He; Yue Gong; Xiaodong Zhang; Jinxi Wei; Zhiyu Dong; Jiexuan Li; Shanchao Zhao; Rui Hou; Wei Zhang; Jigang Wang; Zhijie Li

doi:10.1016/j.apsb.2025.03.039

CDH17-targeting CAR-NK cells synergize with CD47 blockade for potent suppression of gastrointestinal cancers

Acta Pharm Sin B. 2025 May;15(5):2559-2574. doi: 10.1016/j.apsb.2025.03.039. Epub 2025 Mar 19.

Authors

Liuhai Zheng^{1

2}, Youbing Ding^{1

3}, Xiaolong Xu^{1

2}, Huifang Wang^{1

2}, Guangwei Shi⁴, Yang Li¹, Yuanqiao He^{5

6}, Yue Gong¹, Xiaodong Zhang³, Jinxi Wei¹, Zhiyu Dong¹, Jiexuan Li¹, Shanchao Zhao^{7

8

9}, Rui Hou¹, Wei Zhang^{1

10}, Jigang Wang^{1

10

11

12

13

14}, Zhijie Li¹

Affiliations

¹ Department of Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Centre for Geriatrics, Department of Nuclear Medicine, Shenzhen People's Hospital (the First Affiliated Hospital, Southern University of Science and Technology, the Second Clinical Medical College, Jinan University), Shenzhen 518020, China.
² Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou 510632, China.
³ Department of Medical Imaging, the Third Affiliated Hospital of Southern Medical University (Academy of Orthopedics Guangdong Province), Guangzhou 510630, China.
⁴ Department of Neurosurgery & Medical Research Center, Shunde Hospital, Southern Medical University (the First People's Hospital of Shunde Foshan), Guangzhou 510515, China.
⁵ Center of Laboratory Animal Science, Nanchang University, Nanchang 330031, China.
⁶ Key Laboratory of New Drug Evaluation and Transformation of Jiangxi Province, Nanchang 330031, China.
⁷ Department of Urology, the Fifth Affiliated Hospital, Southern Medical University, Guangzhou 510900, China.
⁸ Department of Urology, the Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China.
⁹ Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
¹⁰ Center for Drug Research and Development, Guangdong Provincial Key Laboratory for Research and Evaluation of Pharmaceutical Preparations, Guangdong Pharmaceutical University, Guangzhou 510006, China.
¹¹ State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
¹² Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.
¹³ Department of Traditional Chinese Medicine and School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
¹⁴ State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, Kaifeng 475004, China.

Abstract

Gastrointestinal (GI) cancers are a leading cause of cancer morbidity and mortality worldwide. Despite advances in treatment, cancer relapse remains a significant challenge, necessitating novel therapeutic strategies. In this study, we engineered nanobody-based chimeric antigen receptor (CAR) natural killer (NK) cells targeting cadherin 17 (CDH17) for the treatment of GI tumors. In addition, to enhance the efficacy of CAR-NK cells, we also incorporated CV1, a CD47-SIRPα axis inhibitor, to evaluate the anti-tumor effect of this combination. We found that CDH17-CAR-NK cells effectively eliminated GI cancers cells in a CDH17-dependent manner. CDH17-CAR-NK cells also exhibit potent in vivo anti-tumor effects in cancer cell-derived xenograft and patient-derived xenograft mouse models. Additionally, the anti-tumor activity of CDH17-CAR-NK cells is synergistically enhanced by CD47-signal regulatory protein α (SIRPα) axis inhibitor CV1, likely through augmented macrophages activation and an increase in M1-phenotype macrophages in the tumor microenvironment. Collectively, our findings suggest that CDH17-targeting CAR-NK cells are a promising strategy for GI cancers. The combination of CDH17-CAR-NK cells with CV1 emerges as a potential combinatorial approach to overcome the limitations of CAR-NK therapy. Further investigations are warranted to speed up the clinical translation of these findings.

Keywords: CAR-NK; CD47–SIRPα checkpoint; CDH17; CV1; Gastrointestinal cancers; M1-phenotype macrophages; Macrophage activation; Nanobody.