Cancer biology & medicine · 2026
Metabolic engineering of SLC38A2 reprograms glutamine utilization and enhances CAR-macrophage antitumor function in solid tumors.
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Liu Mingzhu, Chen Qingxi, Zhang Luoling, Zhou Yunxuan, Wen Ning, Jin Jin, Cai Junchao, Su Shicheng, Li Jiang, Zhao Qiyi
Аннотация
OBJECTIVE: This study was aimed at investigating metabolic dysregulation in tumor-associated macrophages (TAMs) in breast cancer and developing a metabolically enhanced chimeric antigen receptor macrophage (CAR-M) strategy to boost antitumor potency in solid tumors.
METHODS: Integrated scRNA-seq and metabolomic analyses were performed to characterize metabolic alterations in macrophages within the breast cancer tumor microenvironment (TME). According to the identified metabolic vulnerabilities, SLC38A2-overexpressing anti-HER2 CAR-Ms were engineered. Glutamine uptake and phagocytic activity were assessed to evaluate functional enhancement.
RESULTS: TAMs in breast cancer exhibited substantial metabolic dysregulation, particularly impaired glutamine metabolism accompanied by decreased expression of the glutamine transporter SLC38A2. Overexpression of SLC38A2 in anti-HER2 CAR-Ms, compared with conventional anti-HER2 CAR-Ms, enhanced glutamine uptake and markedly augmented phagocytosis of HER2+ breast cancer cells.
CONCLUSIONS: Metabolic engineering via SLC38A2 restored glutamine fitness and enhanced the antitumor activity of HER2-targeted CAR-Ms, thus providing a promising strategy to boost CAR-M-mediated tumor suppression in solid tumors.
METHODS: Integrated scRNA-seq and metabolomic analyses were performed to characterize metabolic alterations in macrophages within the breast cancer tumor microenvironment (TME). According to the identified metabolic vulnerabilities, SLC38A2-overexpressing anti-HER2 CAR-Ms were engineered. Glutamine uptake and phagocytic activity were assessed to evaluate functional enhancement.
RESULTS: TAMs in breast cancer exhibited substantial metabolic dysregulation, particularly impaired glutamine metabolism accompanied by decreased expression of the glutamine transporter SLC38A2. Overexpression of SLC38A2 in anti-HER2 CAR-Ms, compared with conventional anti-HER2 CAR-Ms, enhanced glutamine uptake and markedly augmented phagocytosis of HER2+ breast cancer cells.
CONCLUSIONS: Metabolic engineering via SLC38A2 restored glutamine fitness and enhanced the antitumor activity of HER2-targeted CAR-Ms, thus providing a promising strategy to boost CAR-M-mediated tumor suppression in solid tumors.