Researchers at the University of California Los Angeles (UCLA) have developed a new method to boost immune cells with a fuel source that cancerous tumors cannot use, improving their survival and effectiveness in attacking solid tumors in preclinical studies. The findings were published in the journal Cell.
Solid tumors often create an environment where they consume most of the available glucose, depriving T cells—the immune system’s fighters—of the energy needed to function. Dr. Manish Butte, UCLA’s E. Richard Stiehm Professor of Pediatric Allergy, Immunology and Rheumatology and a member of the UCLA Health Jonsson Comprehensive Cancer Center, explained: “A problem with solid tumors is that the immune system tries to fight the cancer, but the tumor cells deplete the key nutrient glucose from their environment. This leaves the T cells that show up to attack with not enough glucose to make cytokines and kill. The balance between tumor cells eating the glucose and the T cells not having enough glucose is a key reason why tumors spread and elude immune attack.”
To address this challenge, researchers provided T cells with cellobiose—a sugar found in plant fiber that is non-toxic and generally considered safe by U.S. regulators. Human cells and tumor cells cannot process cellobiose, but some microbes and fungi can.
The team equipped T cells with two proteins from fungi so they could import cellobiose and convert it into usable glucose inside each cell. In laboratory tests simulating low-glucose conditions typical of tumor environments, these engineered T cells survived longer, continued dividing, produced important cancer-fighting cytokines such as IFN-γ and TNF, and effectively killed tumor cells. Unmodified T cells lost function quickly under similar conditions.
In mouse models of solid cancers, mice treated with these modified T cells showed slower tumor growth and lived longer than those given standard immune cell treatments; some mice experienced complete regression of their tumors.
Analysis showed that engineered T cells within tumors remained more active, proliferated more rapidly, and displayed fewer signs of exhaustion—a common problem limiting immune responses against cancer.
Dr. Matthew Miller, first author of the study and now a postdoctoral fellow at the Salk Institute said: “We demonstrate not only that glucose can be a limiting component of an effective anti-tumor response, but that we can design strategies to bypass the metabolic tug-of-war and deliver a high-value nutrient to T cells engineered with the proprietary metabolic processing system.”
The strategy also worked for human CAR-T cells—immune therapies already used for certain blood cancers—under low-glucose laboratory conditions mimicking those in solid tumors. Cellobiose helped restore CAR-T cell survival, proliferation, cytokine production, and ability to kill tumor targets; similar results were seen in mouse models.
Butte noted: “The survival of T cells in minimal levels of glucose was a huge hint that this was going to work. We saw that when glucose was scarce, the modified T cells used cellobiose to power all the same core energy pathways they normally use glucose for. Their metabolism looked healthy and normal, not starved. Overall, the results demonstrate that providing immune cells with an exclusive, tumor-resistant fuel source enhances their metabolic fitness and anti-tumor activity in solid tumors.”
Researchers believe this approach could help improve many ongoing immunotherapy efforts targeting solid tumors worldwide by reducing problems related to immune cell exhaustion or failure during treatment.
“Our method has the potential to benefit virtually any T cell-based therapy being developed for solid tumors,” Butte said. “That’s what’s most exciting—the broad applicability. We can help a lot of efforts that are already underway.”
Other authors on this study from UCLA include Timothy Thauland, Smriti Nagarajan, Wenqi Ellen Zuo and Miguel Moreno Lastre.
This research received support from several sources including grants from federal agencies such as National Institutes of Health as well as private foundations.
UCLA has been recognized nationally and internationally for its achievements through faculty including Nobel laureates and MacArthur Fellows according to its official website. The university operates within California’s public university system on a 419-acre campus supporting academic excellence across disciplines such as scholarship and research, arts and athletics, while fostering diverse perspectives through inclusive programs and initiatives.
