Boosting BACH2 Protein Expression Enhances CAR-T Cell Efficacy Against Cancer

Researchers at UT Southwestern Medical Center have discovered that increasing the levels of a protein called BACH2 can make engineered anti-cancer immune cells behave more like stem cells, thereby boosting their therapeutic effectiveness. This study, published in Nature Immunology, proposes a new strategy for improving the efficacy of these immune cells, known as Chimeric Antigen Receptor (CAR) T cells.

"Using mouse models of solid cancer, we found that programming CAR-T cells to acquire stem-cell-like properties during the manufacturing process significantly enhances their anti-tumor activity. This fine-tuning of CAR-T cells may represent a powerful strategy to overcome key barriers in solid tumor immunotherapy," said Dr. Tuoqi Wu, who co-led the study with Dr. Chen Yao.

How CAR-T Cells Work and Their Challenges

Since 2017, CAR-T cells have been approved by the U.S. Food and Drug Administration as a cancer therapy. These cells are created by collecting a patient's own T cells and then genetically engineering them to fight that patient's specific cancer.

While CAR-T cells have shown great promise against blood cancers such as leukemia and lymphoma, they only provide durable remission in a portion of cases. Furthermore, CAR-T cells have remained largely ineffective against solid tumors.

This inefficiency stems primarily from a phenomenon called exhaustion, Dr. Wu explained. Constant stimulation by antigens on the surface of cancer cells eventually leaves CAR-T cells unable to fight cancer, proliferate, or respond to immune checkpoint inhibitor drugs. They also exhibit signs of metabolic dysfunction and eventually die. Understanding why exhaustion occurs is key to making CAR-T cells a more effective therapy for all cancers.

The Link Between Stem-Cell-Like Properties and the BACH2 Protein

A few years ago, Dr. Wu and Dr. Yao found an important clue while studying T-cell exhaustion in chronic viral infections. In that research, T cells showed varying tendencies to exhaust. However, the T cells least prone to exhaustion possessed more stem-cell-like properties. Those cells with higher "stemness" produced more of a protein called BACH2.

Figure 1. LT stem-like CAR T cells develop after leukemia clearance and upregulate BACH2 expression. (Hu T, et al., 2026)

To test whether this was also true for CAR-T cells, the researchers cultivated these cells from mice. Much like the previous study, cells with higher BACH2 gene expression maintained more stem-cell-like properties than those with lower expression.

Cells with more BACH2 were also less prone to exhaustion and more resistant to leukemia than cells with less BACH2. The researchers found similar results when observing BACH2 expression in human CAR-T cell samples.

Boosting BACH2 to Improve CAR-T Therapy

Based on these findings, the researchers generated mouse CAR-T cells that produced varying levels of BACH2. The CAR-T cells with the highest BACH2 levels maintained the most stem-cell-like properties and were most resistant to exhaustion when grown in lab cultures.

In another strategy, the researchers transiently increased the amount of BACH2 produced by CAR-T cells during the manufacturing process before injecting them into a mouse model of neuroblastoma—a solid malignancy that develops in nerve precursor cells. Compared to typical CAR-T cells, this adjustment significantly improved the cells' ability to control cancer and inhibited tumor growth.

Dr. Wu and Dr. Yao stated that their study suggests increasing BACH2 production in CAR-T cells may provide a viable technology to help them resist exhaustion while fighting both blood tumors and solid tumors. They hope to eventually test this strategy in clinical trials.