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
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.
Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou 510632, China.
Acta Pharm Sin B. 2025 May;15(5):2559-2574. doi: 10.1016/j.apsb.2025.03.039. Epub 2025 Mar 19.
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-SIRP 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 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 (SIRP) 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.
胃肠道（GI）癌症是全球癌症发病率和死亡率的主要原因。尽管治疗取得了进展，但癌症复发仍然是一个重大挑战，需要新的治疗策略。在本研究中，我们构建了靶向钙黏蛋白17（CDH17）的基于纳米抗体的嵌合抗原受体（CAR）自然杀伤（NK）细胞，用于治疗胃肠道肿瘤。此外，为了提高CAR-NK细胞的疗效，我们还加入了CD47-SIRP轴抑制剂CV1，以评估这种联合用药的抗肿瘤效果。我们发现，CDH17-CAR-NK细胞以CDH17依赖的方式有效消除胃肠道癌细胞。CDH17-CAR-NK细胞在癌细胞衍生的异种移植和患者衍生的异种移植小鼠模型中也表现出强大的抗肿瘤作用。此外，CD47信号调节蛋白（SIRP）轴抑制剂CV1协同增强了CDH17-CAR-NK细胞的抗肿瘤活性，这可能是通过增强巨噬细胞活化以及肿瘤微环境中M1表型巨噬细胞数量增加实现的。总的来说，我们的研究结果表明，靶向CDH17的CAR-NK细胞是治疗胃肠道癌症的一种有前景的策略。CDH17-CAR-NK细胞与CV1的联合使用成为一种潜在的联合方法，以克服CAR-NK疗法的局限性。有必要进行进一步研究，以加快这些研究结果的临床转化。
