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.

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.

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.

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.