{"entity":{"id":"nutrient-competition-tme","kind":"pathway","name":"Nutrient competition & metabolic immunosuppression","aka":[],"tldr":"Tumours and immune cells eat from the same plate. Cancer cells hoard glucose and glutamine, dump lactate and acid, and burn tryptophan and arginine into by-products that paralyse T cells. The tumour wins the food fight, and the immune system loses before it has fired a shot.","summary":"Glycolytic tumour cells deplete glucose, leaving T cells unable to sustain aerobic glycolysis needed for IFN-γ production (Chang et al. 2015); lactate export (MCT4) acidifies the niche, blocks T-cell lactate export and polarises macrophages to M2 (via GPR81, HIF-1α); hypoxia induces adenosine via CD39 → CD73, which signals through A2A receptors to suppress T and NK cells. IDO1 and TDO deplete tryptophan and produce kynurenine, activating AHR in T cells and Tregs (the IDO1 inhibitor epacadostat failed in ECHO-301 with pembrolizumab); arginase-1 from MDSCs and TAMs depletes arginine, which T cells need for proliferation; glutamine depletion and cysteine competition add to the exhaustion. Lipid-laden dendritic cells present antigen poorly. Countermeasures: A2A antagonists and CD73 antibodies (modest), arginase inhibitors, glutamine antagonists that spare T cells (DRP-104), metabolic engineering of CAR-T, and diet interventions in early trials.","asOf":"2026-09-09","wikipedia":"https://en.wikipedia.org/wiki/Tumor_microenvironment","links":[{"label":"Chang et al., Metabolic competition in the tumor microenvironment is a driver of cancer progression (Cell 2015)","url":"https://doi.org/10.1016/j.cell.2015.08.016"}],"tags":["mechanism","mechanics-atlas"],"related":[],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","metabolic-therapy","armored-car","hypoxia-activated-therapy","fasting-mimicking-diet"],"targets":["cd73-adenosine","pd1","csf1r","hif2a","vegf"],"drugs":["epacadostat","pembrolizumab"],"companies":[],"institutions":[],"pathways":["cancer-metabolism","glutamine-metabolism","tumor-microenvironment","hif-vhl","myeloid-suppression-axis"],"terms":["warburg-effect","myeloid-derived-suppressor-cells","tumor-associated-macrophages","cold-vs-hot"],"trials":[],"people":[],"bottlenecks":["b-tme-immunosuppression"],"keyPapers":["paper-chang-cell"],"journals":[],"dependsOn":[],"notes":[],"analogy":"A buffet where the tumour arrives first, eats the protein, and leaves the table sticky with lactate. The immune guests arrive hungry and find nothing but by-products that make them drowsy.","nodes":[{"id":"tum","label":"Glycolytic tumour cell","x":45,"y":12},{"id":"glc","label":"Glucose, glutamine depleted","x":12,"y":35},{"id":"lac","label":"Lactate, acidity (MCT4)","x":45,"y":40},{"id":"ado","label":"CD39 → CD73 → adenosine","x":78,"y":35,"targetId":"cd73-adenosine"},{"id":"ido","label":"IDO1 → kynurenine","x":12,"y":65},{"id":"arg","label":"Arginase (MDSC, TAM)","x":45,"y":68,"targetId":"csf1r"},{"id":"tcell","label":"T-cell / NK dysfunction","x":78,"y":68,"targetId":"pd1"},{"id":"m2","label":"M2 macrophage polarisation","x":78,"y":92},{"id":"hyp","label":"Hypoxia","x":12,"y":92,"targetId":"hif2a"}],"edges":[{"from":"tum","to":"glc","type":"activates"},{"from":"tum","to":"lac","type":"activates"},{"from":"tum","to":"ido","type":"activates"},{"from":"hyp","to":"ado","type":"activates"},{"from":"hyp","to":"tum","type":"activates"},{"from":"glc","to":"tcell","type":"inhibits"},{"from":"lac","to":"tcell","type":"inhibits"},{"from":"lac","to":"m2","type":"activates"},{"from":"ado","to":"tcell","type":"inhibits"},{"from":"ido","to":"tcell","type":"inhibits"},{"from":"arg","to":"tcell","type":"inhibits"}],"interventions":["IDO1 inhibitor epacadostat failed with pembrolizumab in melanoma (ECHO-301); lesson on phase 2 mirages","Adenosine axis: CD73 antibodies (oleclumab) and A2A antagonists, modest activity so far","Arginase inhibitors and glutamine antagonists (DRP-104) designed to spare T cells","Vessel normalisation and hypoxia relief; metabolically armoured CAR-T; diet trials"]},"route":"/pathways/nutrient-competition-tme/","neighbours":{"technology":[{"id":"armored-car","kind":"technology","name":"Armoured, logic-gated & next-gen CARs","route":"/technologies/armored-car/"},{"id":"fasting-mimicking-diet","kind":"technology","name":"Fasting and fasting-mimicking diets around chemotherapy","route":"/technologies/fasting-mimicking-diet/"},{"id":"hypoxia-activated-therapy","kind":"technology","name":"Hypoxia-activated prodrugs","route":"/technologies/hypoxia-activated-therapy/"},{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"},{"id":"metabolic-therapy","kind":"technology","name":"Metabolic therapy: starving the tumour of a nutrient","route":"/technologies/metabolic-therapy/"}],"target":[{"id":"cd73-adenosine","kind":"target","name":"CD73 / adenosine axis","route":"/targets/cd73-adenosine/"},{"id":"csf1r","kind":"target","name":"CSF1R","route":"/targets/csf1r/"},{"id":"hif2a","kind":"target","name":"HIF-2α","route":"/targets/hif2a/"},{"id":"ido1","kind":"target","name":"IDO1","route":"/targets/ido1/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"},{"id":"vegf","kind":"target","name":"VEGF / VEGFR","route":"/targets/vegf/"}],"drug":[{"id":"epacadostat","kind":"drug","name":"Epacadostat","route":"/drugs/epacadostat/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"}],"pathway":[{"id":"cancer-metabolism","kind":"pathway","name":"Cancer metabolism","route":"/pathways/cancer-metabolism/"},{"id":"glutamine-metabolism","kind":"pathway","name":"Glutamine addiction","route":"/pathways/glutamine-metabolism/"},{"id":"myeloid-suppression-axis","kind":"pathway","name":"Myeloid suppression: TAMs, MDSCs & don't-eat-me signals","route":"/pathways/myeloid-suppression-axis/"},{"id":"tumor-microenvironment","kind":"pathway","name":"Tumour microenvironment (TME)","route":"/pathways/tumor-microenvironment/"},{"id":"hif-vhl","kind":"pathway","name":"VHL / HIF oxygen sensing","route":"/pathways/hif-vhl/"}],"term":[{"id":"cold-vs-hot","kind":"term","name":"Hot vs cold tumours","route":"/terms/cold-vs-hot/"},{"id":"metabolic-theory-of-cancer","kind":"term","name":"Metabolic theory of cancer: from Warburg to oncometabolites","route":"/terms/metabolic-theory-of-cancer/"},{"id":"myeloid-derived-suppressor-cells","kind":"term","name":"Myeloid-derived suppressor cells (MDSCs)","route":"/terms/myeloid-derived-suppressor-cells/"},{"id":"tumor-associated-macrophages","kind":"term","name":"Tumour-associated macrophages (TAMs)","route":"/terms/tumor-associated-macrophages/"},{"id":"warburg-effect","kind":"term","name":"Warburg effect","route":"/terms/warburg-effect/"}],"bottleneck":[{"id":"b-tme-immunosuppression","kind":"bottleneck","name":"Cold tumours and the immunosuppressive microenvironment","route":"/bottlenecks/b-tme-immunosuppression/"}],"paper":[{"id":"paper-chang-cell","kind":"paper","name":"Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression","route":"/key-papers/paper-chang-cell/"}]}}