In a groundbreaking advancement that could redefine the landscape of cancer immunotherapy, researchers at UCLA have engineered a novel strategy to empower immune cells with an alternative fuel source impervious to tumor consumption. This pioneering method significantly enhances the survival and tumor-fighting capabilities of T cells within the metabolically hostile microenvironments of solid tumors — including lung, breast, and colorectal cancers — that have historically thwarted the efficacy of immunotherapies such as CAR-T cell treatment.
The challenge of targeting solid tumors with immune-based therapies has long been hampered by a metabolic tug-of-war, where cancer cells voraciously consume glucose, depriving tumor-infiltrating lymphocytes (TILs) of the vital energy substrate required for their function. T cells rely heavily on glucose to fuel their proliferation, cytokine production, and cytotoxicity. When glucose availability plummets in the nutrient-deprived tumor milieu, immune cells become energetically starved, subsequently diminishing their capacity to mount effective anti-tumor responses. This metabolic constraint is a major barrier to successful immunotherapy in solid tumors, allowing cancer cells to evade immune eradication.
To circumvent this metabolic impasse, the UCLA research team ingeniously turned to cellobiose, a disaccharide sugar that is naturally abundant in plant fibers but is metabolically inaccessible to human and tumor cells. Unlike glucose, cellobiose is not absorbed or utilized by mammalian cells or cancer cells, which renders it an ideal exclusive nutrient source to “outsmart” the tumor’s competitive metabolism. Critically, cellobiose is regarded as safe by the U.S. FDA and is already commonly incorporated into various food products, emphasizing its translational potential for clinical applications.
Capitalizing on microbial metabolic pathways, the researchers genetically engineered T cells to express two fungal-derived proteins that enable these cells to import cellobiose and enzymatically convert it intracellularly into glucose. This creative bioengineering provides these T cells an exclusive, tumor-resistant energy supply, effectively bypassing the glucose scarcity imposed by the tumor microenvironment. By appropriating a unique metabolic pathway foreign to mammalian biology, the engineered T cells gain a considerable metabolic advantage in nutrient competition with cancer cells.
In rigorous in vitro experiments designed to simulate the harsh, glucose-depleted conditions present inside solid tumors, the cellobiose-metabolizing T cells demonstrated remarkable metabolic resilience. They maintained cellular viability, sustained proliferation, and robust cytokine production—including key anti-cancer cytokines interferon-gamma (IFN-γ) and tumor necrosis factor (TNF). In stark contrast, unmodified T cells rapidly lost function and succumbed under these nutrient-starved conditions, underscoring the transformative potential of the engineered metabolic adaptation.
Progressing to preclinical mouse models, the enhanced T cells were deployed against established solid tumors. Treatment with the engineered immune cells led to significantly delayed tumor progression and extended survival relative to control groups receiving conventional T cell therapy. Intriguingly, a subset of treated mice exhibited complete tumor regression, highlighting the potent therapeutic promise of this metabolic engineering approach for solid malignancies.
Immunophenotyping within the tumor microenvironment provided further insights; the engineered T cells exhibited heightened activity, increased proliferation, and an improved immunological phenotype characterized by reduced signs of exhaustion. Immune exhaustion, a dysfunctional state marked by decreased effector function and sustained expression of inhibitory receptors, has been a formidable obstacle limiting the efficacy of adoptive cell therapies in cancer. This metabolic strategy, therefore, not only fuels T cell function but may also counteract exhaustion, restoring potent anti-tumor immunity.
A key author of the study, Dr. Matthew Miller, who conducted this research during his doctoral training and now continues as a postdoctoral fellow at the Salk Institute, emphasized that their findings definitively demonstrate how glucose availability is a critical determinant of effective T cell-mediated tumor control. By deploying a proprietary metabolic processing system, immune cells can be selectively provisioned with a nutrient shielded from tumor exploitation, fundamentally altering the battle for metabolic resources in the tumor microenvironment.
Beyond murine models, this intervention was also tested using human CAR-T cells, which have revolutionized the treatment of hematologic cancers but have faced significant hurdles in solid tumor settings. Under physiologically relevant glucose-deprived conditions mimicry in vitro, cellobiose supplementation restored CAR-T cell survival, proliferative capacity, cytokine secretion, and cytotoxic function. In vivo mouse studies further reinforced that CAR-T cells metabolically reprogrammed to utilize cellobiose infiltrated tumors with enhanced vitality and demonstrated promising anti-tumor efficacy.
Senior author Dr. Manish Butte, a distinguished immunologist and oncologist at UCLA, remarked on the remarkable metabolic fitness conferred to the modified T cells. “In the absence of glucose, these T cells engaged cellobiose to power essential metabolic pathways ordinarily dependent on glucose, exhibiting a metabolically healthy phenotype rather than starvation,” he explained. This observation underscores a profound metabolic flexibility elicited by the fungal proteins, enabling immune cells to transcend a fundamental limitation imposed by tumor metabolism.
Importantly, the researchers underscore the broad applicability of this technology across myriad T cell-based immunotherapies, as over 500 ongoing clinical trials worldwide are exploring CAR-T and related treatments for solid tumors—many hampered by immune exhaustion and metabolic failure. The incorporation of these two fungal genes, coupled with controlled systemic delivery of cellobiose, holds promise to universally amplify the efficacy of T cell therapies by overcoming one of the most intractable barriers to solid tumor immunotherapy success.
The team’s multidisciplinary approach, bridging immunology, cancer biology, and metabolic engineering, heralds a new era of metabolic innovation in cancer treatment. Leveraging a naturally abundant, non-toxic sugar inaccessible to cancer cells, they have devised a strategy that effectively grants immune cells a “metabolic sanctuary” within the hostile tumor microenvironment. The potential impact of this research extends far beyond preclinical models, foreshadowing translational applications that could reshape therapeutic paradigms for some of the deadliest solid tumors.
This research was generously supported by esteemed grants from the National Institutes of Health, the E. Richard Stiehm Endowment, the Natasha and Brandon Beck Foundation, and fellowships associated with the UCLA Jonsson Comprehensive Cancer Center. The full scientific report is published in the premier journal Cell (DOI: 10.1016/j.cell.2026.01.015), offering the global biomedical community a detailed description of this visionary metabolic engineering feat.
Moving forward, clinical translation efforts will focus on incorporating this cellobiose metabolism module into next-generation CAR-T cells and other adoptive T cell therapies for solid tumors. Further studies to optimize the delivery and dosing of cellobiose and confirm safety in humans will be paramount. If successful, this innovation may finally unlock the full power of immunotherapy against resistant solid tumors that have thus far defied curative treatment.
This novel metabolic intervention represents an elegant example of bioengineering ingenuity meeting urgent clinical need, illuminating a promising path forward in the war against cancer by fortifying the soldiers of the immune system with an unassailable energy fuel source beyond the reach of their adversaries.
Subject of Research: Cancer immunotherapy, T cell metabolism, CAR-T therapy, solid tumors
Article Title: Tumor-Resistant Sugar Metabolism Enhances T Cell Immunotherapy in Solid Cancers
News Publication Date: 2026
Web References:
- https://www.cell.com/cell/fulltext/S0092-8674(26)00102-9
- http://dx.doi.org/10.1016/j.cell.2026.01.015
Keywords:
Chimeric antigen receptor therapy, Cancer immunology, Cancer immunotherapy, Cancer, Immunology, Cancer research
