Amino Acid Metabolism in Immune Response and Cancer Therapy

Amino acids serve not only as fundamental building blocks for protein synthesis but also as pivotal regulators of immune cell fate, function and anti-tumour activity. Within the tumour microenvironment, cancer cells and infiltrating immune populations engage in a dynamic competition for essential amino acids such as arginine, tryptophan and serine. Dysregulation of transporters and metabolic enzymes alters local concentrations of these nutrients and generates bioactive metabolites that can suppress cytotoxic lymphocytes or polarise myeloid cells toward immunosuppressive phenotypes. Key nutrient-sensing pathways—including the mechanistic target of rapamycin (mTOR) and general control non-derepressible 2 (GCN2) kinase—translate amino acid availability into transcriptional programmes that govern T cell activation, differentiation and exhaustion. Therapeutic strategies aiming to restore or reshape amino acid metabolism range from dietary supplementation and enzyme inhibitors to targeted blockade of transporters and combination with checkpoint blockade. By rewiring metabolic nodes, it is possible to boost effector T cell responses, re-educate suppressive myeloid populations and overcome resistance to existing immunotherapies.

Research from Nature Portfolio

Recent studies have revealed that obesity-associated pancreatic ductal adenocarcinoma is uniquely dependent on mitochondrial arginase 2 for nitrogen disposal. Obesity induces ARG2 expression in tumour cells, driving enhanced flux through the urea cycle and preventing toxic ammonia accumulation. Genetic or pharmacological loss of arginase 2 attenuates tumour growth in murine models, while in vivo isotope tracing demonstrates rerouting of nitrogen into alternative metabolites upon ARG2 inhibition. Analysis of patient samples further indicates that high ARG2 levels correlate with increased body mass index and poor prognosis, highlighting a metabolic vulnerability that could be exploited selectively in obesity-driven cancers without affecting hepatic arginase 1 function.

Amino Acid Metabolism in Immune Response and Cancer Therapy publication trend

The graph below shows the total number of articles in amino acid metabolism in immune response and cancer therapy across all publications each year (not limited to Nature Index journals).

Technical terms

Arginase (ARG1/ARG2): Enzymes that hydrolyse arginine to ornithine and urea, modulating local arginine availability and T cell function.

Myeloid-derived suppressor cells (MDSCs): Immature myeloid cells that accumulate in tumours and suppress T cell responses via nutrient depletion and cytokine production.

Metabolic reprogramming: Adaptive changes in cellular metabolism that support altered energy demands, biosynthesis and signalling in cancer and immune cells.

mTOR (mechanistic target of rapamycin): A central nutrient-sensing kinase that integrates amino acid availability with cell growth, proliferation and immune differentiation.

GCN2 (general control non-derepressible 2): A kinase activated by amino acid deprivation that modulates translation and stress responses in immune cells.

Amino acid transporters: Membrane proteins (for example, LAT1) that import specific amino acids into cells, critical for sustaining effector functions.

References

1. Amino acid metabolism in immune cells: essential regulators of the effector functions, and promising opportunities to enhance cancer immunotherapy. Journal of Hematology & Oncology (2023).
2. Amino acid metabolism reprogramming: shedding new light on T cell anti-tumor immunity. Journal of Experimental & Clinical Cancer Research (2023).
3. Critical role for arginase 2 in obesity-associated pancreatic cancer. Nature Communications (2017).