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

• Published in: Acta pharmaceutica Sinica. B Vol. 15; no. 5; pp. 2559 - 2574
• Main Authors: Zheng, Liuhai, Ding, Youbing, Xu, Xiaolong, Wang, Huifang, Shi, Guangwei, Li, Yang, He, Yuanqiao, Gong, Yue, Zhang, Xiaodong, Wei, Jinxi, Dong, Zhiyu, Li, Jiexuan, Zhao, Shanchao, Hou, Rui, Zhang, Wei, Wang, Jigang, Li, Zhijie
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2025; Elsevier
• Subjects: CAR-NK; CD47–SIRPα checkpoint; CDH17; CV1; Gastrointestinal cancers; M1-phenotype macrophages; Macrophage activation; Nanobody; Original; Nanobody; Gastrointestinal cancers; CD47–SIRPα checkpoint; CAR-NK; Macrophage activation; CDH17; CV1; M1-phenotype macrophages
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2025.03.039

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. CDH17-targeted CAR-NK cells combined with CV1 demonstrate enhanced anti-tumor activity in GI cancers by promoting macrophage activation and increasing M1 macrophage numbers, offering a promising therapeutic strategy. [Display omitted]