Targeting glutamine metabolism enhances CAR-macrophage cancer therapy

Tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) exhibit significant metabolic dysregulation, which impairs their antitumor function. Specifically, their ability to metabolize glutamine, a critical nutrient, is often compromised, limiting their effectiveness in fighting tumors. This metabolic flaw creates a vulnerability that researchers can exploit to enhancechimeric antigen receptor (CAR) macrophages (CAR-Ms) therapy. By focusing on SLC38A2, a glutamine transporter, the study aimed to restore glutamine uptake and improve the performance of CAR-Ms in solid tumor environments. These findings highlight the critical role of metabolic fitness in macrophage functionality and suggest that metabolic engineering could be an essential strategy in optimizing CAR-M therapies. Based on these challenges, further research is needed to explore other metabolic interventions for CAR-M optimization.

Published (DOI: 10.20892/j.issn.2095-3941.2025.0775)in Cancer Biology & Medicine, this study led by researchers from Sun Yat-sen University investigates the metabolic challenges of TAMs in breast cancer. The study focuses on enhancing the function of CAR-Ms by reprogramming their glutamine metabolism through the overexpression of the SLC38A2 transporter. The researchers demonstrated that this metabolic engineering significantly improved macrophage phagocytosis of HER2⁺ tumor cells and enhanced their antitumor activity, offering a promising new approach for CAR-M immunotherapies in solid tumors.

The study utilized integrated single-cell RNA sequencing (scRNA-seq) and metabolomic profiling to reveal significant metabolic dysregulation in TAMs within the breast cancer TME, particularly a defect in glutamine metabolism. The overexpression of SLC38A2, a key glutamine transporter, in anti-HER2 CAR-Ms was engineered to address this issue. The metabolic enhancement resulted in an increased uptake of glutamine and improved macrophage phagocytic activity against HER2⁺ breast cancer cells in vitro. This metabolic reprogramming also led to increased mitochondrial fragmentation and enhanced macrophage activation, reflected by elevated expression of costimulatory molecules such as CD80 and CD86. Furthermore, the engineered CAR-Ms demonstrated greater cytokine production, including pro-inflammatory cytokines like TNF-α, which further amplified the antitumor immune response. In vivo experiments using mouse models of HER2⁺ breast cancer showed that SLC38A2/anti-HER2 CAR-Ms significantly suppressed tumor growth compared to conventional CAR-Ms, confirming the therapeutic potential of this metabolic strategy. These results indicate that targeting glutamine metabolism can boost CAR-M efficacy, offering a promising new avenue for CAR-M-based immunotherapy.

"By engineering CAR-macrophages to optimize their metabolic pathways, we can significantly enhance their antitumor activity," said Dr. Qiyi Zhao, one of the lead researchers. "Our findings underscore the importance of metabolic reprogramming in immune cell function, particularly in the context of solid tumors. This approach not only improves macrophage effector functions but also supports broader immune responses, such as CD8⁺ T-cell activation, providing a dual benefit for cancer treatment. The potential to enhance CAR-M therapies via metabolic strategies marks an exciting frontier in cancer immunotherapy."

This study introduces a groundbreaking method to enhance CAR-M therapies by targeting metabolic pathways. The integration of metabolic engineering into CAR-M design could be a game-changer for solid tumor treatments, where traditional therapies often face significant challenges, including limited tumor penetration and immunosuppressive environments. The ability to reprogram macrophage metabolism, particularly glutamine utilization, opens new possibilities for improving the effectiveness and persistence of CAR-Ms in the TME. This approach could be extended to other solid tumors, offering a potential strategy to optimize CAR-M-based therapies across a wide range of cancers. Future research will focus on validating these results in diverse tumor models and investigating other metabolic vulnerabilities within the TME.