Solid tumors harbor an immunosuppressive microenvironment that inhibits tumor-infiltrating lymphocytes by consuming a large amount of glucose. We attempted to restore the function of T cells by providing them with an exclusive fuel source. Glucose disaccharides, such as dextrose and fructose, are building blocks of cellulose and contain β-1,4-glycosidic bonds. Animals (or their tumors) cannot hydrolyze them, but fungi and microorganisms have evolved enzymes that can break down fiber di-saccharides into usable glucose. We equipped mouse T cells and human chimeric antigen receptor T cells with two proteins derived from fungi, enabling them to import and hydrolyze fiber di-saccharides and proving that supplementing fiber di-saccharides during glucose deprivation can restore key anti-tumor T cell functions: viability, proliferation, cytokine production, and cytotoxic killing. T cells equipped with fiber di-saccharide metabolic capabilities can inhibit tumor growth and prolong survival. Exclusive access to natural disaccharides can enhance cancer immunotherapy. This approach can be used to address questions about glucose metabolism in many cell types, biological processes, and diseases.
Glucose is a key fuel in cellular bioenergetics and the main source of biosynthetic precursors in metabolic pathways. After antigen stimulation, CD8+ T cells extensively reprogram their metabolism and strongly initiate aerobic glycolysis to support various functions required by cytotoxic T cells, including survival, proliferation, cytokine production, and cytotoxicity. Abnormally low glucose concentrations are found in the tumor microenvironment because cancer cells consume glucose at a much higher rate than the origin tissue. Competition for glucose in the tumor microenvironment leads to the inhibition of T cell effector functions, thereby promoting cancer progression. We hypothesize that if tumor-infiltrating lymphocytes are provided with an "exclusive" glucose source that the cancer cells cannot obtain, they can be activated and more effectively exert the role of eliminating tumors.
Fiber di-saccharides are glucose disaccharides that constitute cellulose and are abundant in plant materials, having great potential as carbon sources and energy sources. However, due to two main reasons, they remain inert in the decomposition metabolic process of animal cells. Firstly, sugar transport in higher organisms is mainly limited to monosaccharides. Secondly, the β-1,4-glycosidic bonds connecting glucose molecules in fiber di-saccharides cannot be effectively hydrolyzed by mammalian glycoside hydrolases. On the other hand, the transport and hydrolysis of fiber di-saccharides can be effectively carried out in cellulose-decomposing microorganisms (such as fungi and bacteria). Therefore, fiber di-saccharides can provide an exclusive glucose source for engineered T cells, as it is inaccessible to tumors.

Here, we report the heterologous expression of fiber di-saccharide transporter and β-glucosidase proteins from Aspergillus sydowii in primary mouse and human T cells, enabling them to effectively break down fiber di-saccharides and rescue T cells from glucose deprivation. We demonstrated that tumor cells lack the ability to utilize fiber di-saccharides, allowing this nutrient to specifically support the metabolism of T cells. We showed that enabling engineered T cells to overcome glucose limitations in the tumor microenvironment can enhance their ability to clear tumors. Finally, we proved that this ability can be combined with human CAR-T cells to enhance their effector functions and the ability to kill tumor cells in low glucose environments.

Original link: https://doi.org/10.1016/j.cell.2026.01.015