Although T cell–based therapies have shown great promise for treatment of hematologic malignancies, many barriers limit their success in solid tumor types. One such limitation is the scarcity of energy sources, like glucose, within the solid tumor microenvironment that fuel effector processes. Miller and colleagues designed a unique strategy to address this by equipping T cells with the machinery necessary to catabolize cellobiose, a glucose disaccharide that is otherwise inert in mammalian cells. Vectors were adapted from Neurospora crassa, mold containing two proteins necessary for cellobiose processing: a transporter (CDT-1) and a β-glucosidase (GH1-1) for hydrolysis. Transduction of these genes into mouse T cells, referred to hereafter as CG-T cells, conferred T cells the ability to import and utilize cellobiose to produce glucose for use in downstream metabolic pathways. Isotope tracing demonstrated that carbon-labeled cellobiose and glucose yielded similar intracellular metabolic profiles in CG-T cells. Importantly, detected metabolites contained negligible traces of 13C-cellobiose in non-transduced T cells, further emphasizing the specificity of the engineered system. Functional in vitro analyses revealed that, in transduced cells, cellobiose also restored proliferation and cytokine production that was diminished in low glucose conditions. To evaluate the impact on antitumor activity in vivo, CG-T cells were adoptively transferred into immunocompetent mice bearing subcutaneous lymphomas. Interestingly, animals treated thrice daily with intraperitoneal cellobiose exhibited a marked survival benefit when compared with PBS-treated controls. In the context of human T-cell biology, CAR T cells were also transduced with CDT-1 and GH1-1 viruses (CAR-CG-T cells). As observed in the mouse system, glucose withdrawal impaired CAR-CG-T cell proliferation, which was restored in the presence of cellobiose. When co-cultured with human lymphoma cells under low glucose conditions, cellobiose supplementation also rescued cytokine production and cytotoxic ability of CAR-CG-T cells. In summary, this study suggests that T cells can be engineered to leverage cellobiose as an exclusive fuel source that circumvents glucose deprivation in the tumor microenvironment and supports cytotoxic immune activity.Miller ML, Thauland TJ, Nagarajan SS, Zuo WE, Moreno Lastre MA, Butte MJ. Fungal-derived cellobiose metabolic pathway fuels T cells to bypass intratumoral glucose competition. Cell 2026;189:1717–30.Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.
A Mon, study studied this question.