Metabolic Interactions in Tumor Immunology

The interplay between tumour metabolism and immune function shapes the efficacy of anticancer responses. Tumour cells reprogramme core pathways such as glycolysis and fatty acid oxidation to sustain rapid proliferation and to generate oncometabolites that modulate the local milieu. This metabolic rewiring creates competition for nutrients in the tumour microenvironment, often leading to nutrient scarcity, hypoxia and accumulation of waste products such as lactate. Immune cells, particularly cytotoxic CD8+ T cells, must adapt their own metabolic programmes to differentiate, expand and exert effector functions. Checkpoint molecules can further alter these programmes, inhibiting glycolysis or redirecting energy flux towards lipid oxidation. Understanding how metabolic crosstalk influences T-cell activation, persistence and exhaustion has become central to improving immunotherapy. By targeting metabolic checkpoints—either in tumour cells to alleviate immunosuppression or in T cells to bolster resilience—it may be possible to enhance antitumour immunity and achieve durable clinical benefit.

Research from Nature Portfolio

Recent studies have shown that a dietary lipid, trans-vaccenic acid, directly enhances CD8+ T-cell effector function and antitumour immunity by antagonising a G protein–coupled receptor and activating a cAMP–PKA–CREB signalling axis in vivo. This mechanism highlights a host-extrinsic route to metabolic reprogramming of T cells. Another investigation has revealed that lactate, long considered merely a metabolic by-product, can increase the stemness of intratumoural CD8+ T cells. Lactate inhibits histone deacetylase activity, leading to epigenetic acetylation at a key enhancer of the Tcf7 locus and expansion of TCF-1+ stem-like T cells with improved recall capacity. Foundational work on immune checkpoints has also elucidated how engagement of the inhibitory receptor PD-1 suppresses glycolysis and amino acid metabolism in T cells while promoting fatty acid β-oxidation via upregulation of CPT1A and lipolytic enzymes, thereby explaining both T-cell longevity under chronic antigen exposure and sensitivity to checkpoint blockade.

Metabolic Interactions in Tumor Immunology publication trend

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

Technical terms

Tumour microenvironment: The cellular and molecular milieu surrounding tumour cells, comprising stromal cells, immune infiltrates, blood vessels and soluble factors.

Metabolic reprogramming: The alteration of intracellular metabolic pathways to meet the bioenergetic and biosynthetic demands of cells.

Effector CD8+ T cell: A cytotoxic lymphocyte that recognises and destroys malignant or infected cells through release of cytolytic granules and cytokines.

Oncometabolite: A metabolite produced or accumulated in tumour cells that promotes oncogenesis or immune evasion.

Histone deacetylase (HDAC): An enzyme that removes acetyl groups from histone proteins, leading to chromatin condensation and transcriptional repression.

Fatty acid oxidation (FAO): The mitochondrial breakdown of fatty acids to generate acetyl-CoA for energy production via the tricarboxylic acid cycle.

Spare respiratory capacity: The extra mitochondrial oxidative phosphorylation capacity available to cells under stress or increased workload.

References

1. Signaling pathways in cancer metabolism: mechanisms and therapeutic targets. Signal Transduction and Targeted Therapy (2023).
2. Trans-vaccenic acid reprograms CD8+ T cells and anti-tumour immunity. Nature (2023).
3. Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy. Cell (2024).
4. Cancer immunometabolism: advent, challenges, and perspective. Molecular Cancer (2024).
5. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nature Communications (2015).
6. The tumor microenvironment as a metabolic barrier to effector T cells and immunotherapy. eLife (2020).
7. Lactate increases stemness of CD8 + T cells to augment anti-tumor immunity. Nature Communications (2022).