Methionine Metabolism in Cancer Immunology

Methionine lies at the heart of one-carbon metabolism, supplying methyl groups for DNA, RNA and histone modifications that govern gene expression in both tumour and immune cells. Cancer cells often exhibit enhanced methionine uptake and recycling, creating a nutrient-depleted microenvironment that compromises antitumour immunity. Within T lymphocytes, methionine availability regulates S-adenosylmethionine (SAM) pools and downstream epigenetic marks, which in turn control effector differentiation, cytokine production and the expression of inhibitory receptors. Conversely, dietary or enzymatic methionine restriction can reprogramme systemic sulphur metabolism, perturb gut microbial production of hydrogen sulphide and impair T-cell survival and activation. These insights position methionine metabolism as a metabolic checkpoint in cancer immunology, offering multiple entry points for intervention: targeting tumour methionine transporters, modulating SAM-cycle enzymes or fine-tuning dietary methionine intake. Such strategies hold promise for enhancing the efficacy of immune checkpoint inhibitors and for mitigating resistance mechanisms, with broad implications for patient stratification and combination therapies.

Research from Nature Portfolio

Recent studies have shown that competition for methionine within the tumour microenvironment drives T-cell exhaustion. One investigation revealed that cancer cell–mediated methionine uptake via the transporter SLC43A2 deprives CD4+ T cells of methionine, diminishing SAM levels, reducing histone H3K79 dimethylation and downregulating AMPK, thereby upregulating PD-1 and impairing antitumour function. Restoration of methionine availability or genetic ablation of SLC43A2 reinstates epigenetic control, reduces PD-1 expression and revives CD4+ T-cell activity. Another study addressed the consequences of dietary methionine restriction in immunocompetent models. While methionine-restricted diets inhibit tumour growth in immunodeficient hosts, they paradoxically reduce circulating T-cell numbers and compromise immunotherapy responses in mice with intact immunity. Mechanistically, reduced methionine intake lowers microbial hydrogen sulphide production, a critical pro-survival signal for T cells. Supplementation with a sulphide donor or methionine restores antitumour immunity and reverses tumour progression, underscoring the necessity of balancing nutritional interventions with immune competence.

Methionine Metabolism in Cancer Immunology publication trend

The graph below shows the total number of articles in methionine metabolism in cancer immunology across all publications each year (not limited to Nature Index journals).

Technical terms

S-adenosylmethionine (SAM): the principal methyl donor generated from methionine, essential for DNA, RNA and histone methylation.

PD-1: programmed cell death protein 1, an inhibitory receptor on T cells that marks exhaustion and limits effector function.

T-cell exhaustion: a dysfunctional state of T lymphocytes characterised by sustained expression of inhibitory receptors and diminished cytokine production.

SLC43A2: a transmembrane amino acid transporter that mediates methionine uptake in tumour and immune cells.

H3K79me2: dimethylation of histone 3 at lysine 79, an epigenetic mark linked to active gene transcription.

Gut microbiota: the community of microorganisms in the gastrointestinal tract, which influences host immunity through metabolite production such as hydrogen sulphide.

References

1. Methionine consumption by cancer cells drives a progressive upregulation of PD-1 expression in CD4 T cells. Nature Communications (2023).
2. Methionine restriction-induced sulfur deficiency impairs antitumour immunity partially through gut microbiota. Nature Metabolism (2023).
3. Antigen receptor control of methionine metabolism in T cells. eLife (2019).
4. Unveiling the methionine cycle: a key metabolic signature and NR4A2 as a methionine-responsive oncogene in esophageal squamous cell carcinoma. Cell Death & Differentiation (2024).