# Nutrient competition & metabolic immunosuppression

Source: https://onco.cc/pathways/nutrient-competition-tme/  
OnCo record `nutrient-competition-tme` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Pathway
- Last checked: 2026-09-09
- Tags: mechanism; mechanics-atlas
- 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.
- 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

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Tumor_microenvironment
- Chang et al., Metabolic competition in the tumor microenvironment is a driver of cancer progression (Cell 2015): https://doi.org/10.1016/j.cell.2015.08.016

## Connected records

- technologies: [Armoured, logic-gated & next-gen CARs](https://onco.cc/technologies/armored-car/), [Fasting and fasting-mimicking diets around chemotherapy](https://onco.cc/technologies/fasting-mimicking-diet/), [Hypoxia-activated prodrugs](https://onco.cc/technologies/hypoxia-activated-therapy/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [Metabolic therapy: starving the tumour of a nutrient](https://onco.cc/technologies/metabolic-therapy/)
- targets: [CD73 / adenosine axis](https://onco.cc/targets/cd73-adenosine/), [CSF1R](https://onco.cc/targets/csf1r/), [HIF-2α](https://onco.cc/targets/hif2a/), [IDO1](https://onco.cc/targets/ido1/), [PD-1](https://onco.cc/targets/pd1/), [VEGF / VEGFR](https://onco.cc/targets/vegf/)
- drugs: [Epacadostat](https://onco.cc/drugs/epacadostat/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/)
- pathways: [Cancer metabolism](https://onco.cc/pathways/cancer-metabolism/), [Glutamine addiction](https://onco.cc/pathways/glutamine-metabolism/), [Myeloid suppression: TAMs, MDSCs & don't-eat-me signals](https://onco.cc/pathways/myeloid-suppression-axis/), [Tumour microenvironment (TME)](https://onco.cc/pathways/tumor-microenvironment/), [VHL / HIF oxygen sensing](https://onco.cc/pathways/hif-vhl/)
- terms: [Hot vs cold tumours](https://onco.cc/terms/cold-vs-hot/), [Metabolic theory of cancer: from Warburg to oncometabolites](https://onco.cc/terms/metabolic-theory-of-cancer/), [Myeloid-derived suppressor cells (MDSCs)](https://onco.cc/terms/myeloid-derived-suppressor-cells/), [Tumour-associated macrophages (TAMs)](https://onco.cc/terms/tumor-associated-macrophages/), [Warburg effect](https://onco.cc/terms/warburg-effect/)
- bottlenecks: [Cold tumours and the immunosuppressive microenvironment](https://onco.cc/bottlenecks/b-tme-immunosuppression/)
- key papers: [Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression](https://onco.cc/key-papers/paper-chang-cell/)

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