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Cell-programmed nutrient partitioning in the tumour microenvironment


Reinfeld BIBradley I , Madden MZMatthew Z , Wolf MMMelissa M , Chytil AAnna , Bader JEJackie E , Patterson ARAndrew R , Sugiura AAyaka , Cohen ASAllison S , Ali AAhmed , Do BTBrian T , Muir AAlexander , Lewis CACaroline A , Hongo RARachel A , Young KLKirsten L , Brown RERachel E , Todd VMVera M , Huffstater TTessa , Abraham AAbin , O'Neil RTRichard T , Wilson MHMatthew H , Xin FFuxue , Tantawy MNM Noor , Merryman WDW David , Johnson RWRachelle W , Williams CSChristopher S , Mason EFEmily F , Mason FMFrank M , Beckermann KEKatherine E , Vander Heiden MGMatthew G , Manning HCH Charles , Rathmell JCJeffrey C , Rathmell WKW Kimryn . Nature. 2021 4 7; 593(7858). 282-288


Cancer cells characteristically consume glucose through Warburg metabolism, a process that forms the basis of tumour imaging by positron emission tomography (PET). Tumour-infiltrating immune cells also rely on glucose, and impaired immune cell metabolism in the tumour microenvironment (TME) contributes to immune evasion by tumour cells. However, whether the metabolism of immune cells is dysregulated in the TME by cell-intrinsic programs or by competition with cancer cells for limited nutrients remains unclear. Here we used PET tracers to measure the access to and uptake of glucose and glutamine by specific cell subsets in the TME. Notably, myeloid cells had the greatest capacity to take up intratumoral glucose, followed by T cells and cancer cells, across a range of cancer models. By contrast, cancer cells showed the highest uptake of glutamine. This distinct nutrient partitioning was programmed in a cell-intrinsic manner through mTORC1 signalling and the expression of genes related to the metabolism of glucose and glutamine. Inhibiting glutamine uptake enhanced glucose uptake across tumour-resident cell types, showing that glutamine metabolism suppresses glucose uptake without glucose being a limiting factor in the TME. Thus, cell-intrinsic programs drive the preferential acquisition of glucose and glutamine by immune and cancer cells, respectively. Cell-selective partitioning of these nutrients could be exploited to develop therapies and imaging strategies to enhance or monitor the metabolic programs and activities of specific cell populations in the TME.