Enhancing tumor-infiltrating T cells with an exclusive fuel source

Summary Solid tumors harbor immunosuppressive microenvironments that inhibit tumor-infiltrating lymphocytes (TILs) through the voracious consumption of glucose. We sought to restore TIL function by providing them with an exclusive fuel source. The glucose disaccharide cellobiose, which is the building block of cellulose, contains a β-1,4-glycosidic bond that that animals (or their tumors) cannot hydrolyze, but microbes have evolved enzymes to catabolize cellobiose into useful glucose. We equipped mouse T cells and human CAR-T cells with two proteins enabling import and hydrolysis of cellobiose and demonstrated that cellobiose supplementation during glucose withdrawal restores key anti-tumor T-cell functions: viability, proliferation, cytokine production, and cytotoxic killing. Engineered T cells offered cellobiose suppress murine tumor growth and prolong survival. Offering exclusive access to a natural disaccharide is a new tool that augments cancer immunotherapies. This approach could be used to answer questions about glucose metabolism across many cell types, biological processes, and diseases.