Metabolic engineering of SLC38A2 reprograms glutamine utilization and enhances CAR-macrophage antitumor function in solid tumors

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.