近日，美国耶鲁大学医学院陈斯迪及其团队的论文发现了OR7A10 GPCR工程促进CAR-NK治疗实体肿瘤。这一研究成果发表在2026年2月25日出版的国际学术期刊《自然》上。

为了确定增强CAR-NK细胞功效的功能获得靶点，课题组在原代人CAR-NK细胞中进行了无偏倚的体内CRISPR激活筛选，然后进行了条形码靶向的体内开放阅读框筛选。研究小组鉴定并全面验证了OR7A10、G蛋白偶联受体（GPCR）作为首选。用OR7A10 cDNA修饰CAR-NK细胞（一种与CRISPR无关的方法，具有简单的制造策略）增强了它们的增殖、活化、脱颗粒、细胞因子产生、死亡配体表达、趋化因子受体表达、细胞毒性、持久性、代谢适应度和肿瘤微环境抗性。

此外，来自多个外周血和脐带血献血者的原代人NK细胞的衰竭减少。OR7A10功能获得性CAR-NK细胞在多种实体肿瘤模型中显示出强大的体内功效。例如，在原位乳腺癌无主模型中实现了100%的完全缓解，长期肿瘤控制和生存获益。这些发现确立了OR7A10工程CAR-NK细胞作为一种高效、可扩展的实体肿瘤治疗药物。

研究人员表示，嵌合抗原受体(CAR)-自然杀伤（NK）细胞疗法有望治疗实体肿瘤，但由于肿瘤在肿瘤微环境中的浸润性、持久性和耐药性较差，因此仍然受到限制。

附：英文原文

Title: OR7A10 GPCR engineering boosts CAR-NK therapy against solid tumours

Author: Yang, Luojia, Renauer, Paul A., Tang, Kaiyuan, Saskin, Josh, Zhou, Liqun, Zou, Charles, Lee, Seok-Hoon, Fox, Madison, Johnson-Noya, Samuel, Weiss, Benedict, Deng, Stephanie, Fang, Paris, Chen, Binfan, Sferruzza, Giacomo, Fooladi, Saba, Zhao, Kai, Park, Daniel, Zhang, Feifei, Tu, Jiayi, Chen, Jing, Moliterno, Jennifer, Gunel, Murat, Peng, Lei, Chen, Sidi

Issue&Volume: 2026-02-25

Abstract: Chimeric antigen receptor (CAR)-natural killer (NK) cell therapies hold promise for solid tumours but remain limited because of poor tumour infiltration, persistence and resistance in the tumour microenvironment1,2,3,4. Here, to identify gain-of-function targets that enhance CAR-NK cell efficacy, we performed an unbiased in vivo CRISPR activation screen followed by a barcoded targeted in vivo open reading frame screen in primary human CAR-NK cells. We identified and comprehensively validated OR7A10, a Gprotein-coupled receptor (GPCR), as the top candidate. Engineering CAR-NK cells with OR7A10 cDNA (a CRISPR-independent method with a simple manufacturing strategy) enhanced their proliferation, activation, degranulation, cytokine production, death ligand expression, chemokine receptor expression, cytotoxicity, persistence, metabolic fitness and tumour microenvironment resistance. Moreover, exhaustion in primary human NK cells derived from multiple peripheral blood and cord blood donors was reduced. OR7A10 gain-of-function CAR-NK cells displayed strong in vivo efficacy across multiple solid tumour models. For example, 100% complete response with long-term tumour control and survival benefit in an orthotopic breast cancer mouse model were achieved. These findings establish OR7A10-engineered CAR-NK cells as a highly potent and scalable off-the-shelf therapeutic for solid tumours.

DOI: 10.1038/s41586-026-10149-8

Source: https://www.nature.com/articles/s41586-026-10149-8