Metabolic Engineering Boosts Cancer-Fighting Immune Cells

A new study reveals that reprogramming the metabolism of engineered immune cells can significantly enhance their ability to attack breast tumors. Researchers from Sun Yat-sen University have found a way to improve the function of chimeric antigen receptor macrophages (CAR-Ms) by addressing a key metabolic deficiency common in the tumor microenvironment.

The research, published in Cancer Biology & Medicine, focused on overcoming the immunosuppressive conditions within solid tumors, which often impair immune cell activity.

"By engineering CAR-macrophages to optimize their metabolic pathways, we can significantly enhance their antitumor activity. Our findings underscore the importance of metabolic reprogramming in immune cell function, particularly in the context of solid tumors," stated Dr. Qiyi Zhao, one of the lead researchers.

The Metabolic Challenge in Tumors

The team began by analyzing the tumor microenvironment in breast cancer. Using integrated single-cell RNA sequencing and metabolomic profiling, they identified significant metabolic dysregulation in tumor-associated macrophages (TAMs). A central finding was a specific defect in glutamine metabolism, a process crucial for cell function and energy.

Engineering a Solution: The SLC38A2 Transporter

To address this, the scientists engineered anti-HER2 CAR-Ms to overexpress SLC38A2, a primary transporter for glutamine. This modification aimed to directly counter the metabolic limitations observed in the tumor setting.

The results were striking. In laboratory tests, the modified CAR-Ms showed:

• Increased glutamine uptake.
• Improved phagocytic activity against HER2-positive breast cancer cells.
• Greater production of pro-inflammatory cytokines like TNF-α.
• Elevated expression of costimulatory molecules (CD80 and CD86), which are vital for activating other immune cells.

The metabolic shift also led to changes in the cells' power sources, including increased mitochondrial fragmentation.

Promising Results in Animal Models

The most critical test came in mouse models of HER2-positive breast cancer. Here, the SLC38A2-enhanced CAR-Ms significantly suppressed tumor growth compared to conventional CAR-Ms.

According to the researchers, this approach does more than just improve the macrophages' own cancer-killing ability. It also helps support broader immune responses, including the activation of CD8+ T-cells, which are another powerful line of defense against cancer.

Implications and Future Directions

The study positions metabolic engineering as a promising strategy for optimizing next-generation CAR-M therapies for solid tumors, which have been challenging to treat with existing immunotherapies.

• The approach could potentially be extended to other types of solid tumors beyond breast cancer.
• Future research will focus on validating these results in more diverse tumor models.
• Scientists also plan to investigate other metabolic vulnerabilities within tumor microenvironments that could be targeted to boost immune cell function.

DOI: 10.20892/j.issn.2095-3941.2025.0775