UCLA Researchers Engineer T Cells to Overcome Glucose Starvation in Solid Tumors Using Cellobiose Metabolism
Key Insights
UCLA researchers have developed a breakthrough method to fuel T cells with cellobiose, a plant-derived sugar that tumors cannot consume, dramatically improving immune cell survival and anti-tumor activity in solid cancers.
The engineered T cells, equipped with two fungal proteins, can convert cellobiose into glucose internally while bypassing the metabolic competition with cancer cells that typically starves immune responses.
In preclinical studies, the cellobiose-powered T cells showed enhanced survival, cytokine production, and tumor-killing ability, with some mice experiencing complete tumor regression.
UCLA researchers have engineered a revolutionary approach to overcome one of cancer immunotherapy's most persistent challenges: the metabolic starvation of immune cells within solid tumors. Published in the journal Cell, their breakthrough method equips T cells with an alternative fuel source that cancer cells cannot steal, dramatically improving their survival and tumor-fighting capabilities in preclinical studies.
The research addresses a fundamental problem that has limited the effectiveness of CAR-T and other immunotherapies in solid tumors such as lung, breast, and colorectal cancer. "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," explained senior author Dr. Manish Butte, UCLA's E. Richard Stiehm Professor of Pediatric Allergy, Immunology and Rheumatology. "This leaves the T cells that show up to attack with not enough glucose to make cytokines and kill."
Novel Cellobiose-Based Fuel System
To overcome this metabolic roadblock, the team turned to cellobiose, a naturally occurring sugar found in plant fiber that is non-toxic and FDA-approved for food use. Crucially, human cells and tumors cannot break down cellobiose, making it an ideal exclusive nutrient source for engineered immune cells.
The researchers genetically modified T cells with two proteins derived from fungi, enabling the immune cells to import cellobiose and convert it into usable glucose internally. This creative bioengineering provides T cells with an exclusive, tumor-resistant energy supply that bypasses the glucose scarcity imposed by the tumor microenvironment.
Dramatic Improvements in Laboratory Studies
In laboratory experiments designed to mimic nutrient-poor tumor environments, where glucose levels can fall to a fraction of healthy tissue levels, the engineered T cells demonstrated remarkable resilience. They maintained cellular viability, sustained proliferation, and robust production of cancer-fighting cytokines including interferon-gamma (IFN-γ) and tumor necrosis factor (TNF). In stark contrast, unmodified T cells rapidly lost function under these nutrient-starved conditions.
"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," said first author Dr. Matthew Miller, a former doctoral student in Dr. Butte's lab and now a postdoctoral fellow at the Salk Institute.
Promising Results in Mouse Models
The strategy proved effective in mouse models of solid cancer. Mice treated with tumor-targeted T cells capable of metabolizing cellobiose showed slower tumor growth and lived significantly longer than those receiving standard immune cells. Some mice experienced complete tumor regression.
When researchers examined immune cells inside the tumors, they found that the engineered T cells were more active and proliferative and showed fewer signs of exhaustion, a dysfunctional state that limits immune responses in many cancers.
Enhanced CAR-T Cell Performance
The approach also showed promise for human CAR-T cells, which are already used for certain leukemias and lymphomas but have faced significant hurdles in solid tumor settings. In low-glucose laboratory conditions similar to those found in solid tumors, cellobiose restored CAR-T cell survival, proliferation, cytokine production, and tumor-killing ability. In mouse models, CAR-T cells given access to cellobiose were more active inside tumors and showed a strong trend toward improved tumor control.
"The survival of T cells in minimal levels of glucose was a huge hint that this was going to work," Butte said. "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."
Broad Clinical Implications
The researchers emphasize the broad applicability of this technology across multiple T cell-based immunotherapies. With more than 500 clinical trials worldwide currently testing CAR-T cells in solid tumors, many struggling with immune cell exhaustion and failure, this metabolic engineering approach could have widespread impact.
"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."
The work was supported by grants from the National Institutes of Health, the E. Richard Stiehm Endowment, the Natasha and Brandon Beck Foundation, the UCLA Jonsson Comprehensive Cancer Center Fellowship, and the National Institutes of Health Ruth L. Kirschstein National Research Service Award. Other authors include Timothy Thauland, Smriti Nagarajan, Wenqi Ellen Zuo, and Miguel Moreno Lastre, all from UCLA.