Metabolic Reprogramming in Tumor Immunology

Metabolic reprogramming in tumor immunology refers to alterations in nutrient uptake and intracellular pathways that enable both cancer cells and immune cells to survive, proliferate and exert specific functions within the tumour microenvironment. Cancer cells frequently adopt aerobic glycolysis, lipid synthesis and altered amino acid metabolism to support rapid growth, generating a milieu rich in lactate, fatty acids and reactive oxygen species. Immune cells such as tumour-associated macrophages (TAMs), myeloid-derived suppressor cells and effector T lymphocytes sense and respond to these metabolic cues, undergoing their own rewiring that can either bolster antitumour immunity or promote immunosuppression. For example, TAMs may switch between glycolytic, pro-inflammatory phenotypes and oxidative, immunosuppressive states, while CD8+ T cells face metabolic stress that drives exhaustion and impairs cytotoxicity. Understanding the cross-talk between tumour metabolism and immune reprogramming has uncovered targets in glycolysis, fatty acid oxidation and cholesterol transport that hold promise for enhancing the efficacy of immunotherapies and reshaping the immune landscape of solid tumours.

Research from Nature Portfolio

Recent studies have exploited oncolytic viral platforms to modulate cholesterol homeostasis in glioblastoma, demonstrating that enforced cholesterol efflux in tumour-associated macrophages restores their phagocytic capacity and reinvigorates T cell-mediated antitumour immunity. By delivering a cholesterol transporter within an oncolytic adenovirus, researchers achieved long-term immune surveillance and tumour regression in preclinical models. Complementary work has identified monoacylglycerol lipase deficiency in TAMs as a driver of lipid overload, which in turn promotes cannabinoid receptor-mediated immunosuppression and inhibits CD8+ T cell function. Therapeutic blockade of this lipid-accumulation axis reprogrammes macrophages toward a tumour-fighting state, underscoring lipid metabolism as a regulator of macrophage activation and a target for adjuvant immunotherapy.

Metabolic Reprogramming in Tumor Immunology publication trend

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

Technical terms

Metabolic reprogramming: The process by which cells adjust nutrient uptake and intracellular pathways to meet altered energetic or biosynthetic demands.

Tumour microenvironment (TME): The dynamic milieu surrounding a tumour, comprising immune cells, stromal cells, extracellular matrix and soluble factors.

Tumour-associated macrophages (TAMs): A heterogeneous population of macrophages within the TME that can adopt pro-inflammatory or immunosuppressive phenotypes.

Fatty acid oxidation (FAO): A mitochondrial pathway that degrades fatty acids to generate acetyl-CoA, NADH and FADH₂ for energy production.

Cholesterol efflux: The transport of cholesterol out of cells, often mediated by transporters that maintain lipid homeostasis and influence immune cell function.

Effector T cells: Activated T lymphocytes that perform cytotoxic or helper functions to eliminate infected or malignant cells.

References

1. Metabolism, metabolites, and macrophages in cancer. Journal of Hematology & Oncology (2023).
2. Linoleic acid potentiates CD8+ T cell metabolic fitness and antitumor immunity. Cell Metabolism (2023).
3. Oncolytic viruses engineered to enforce cholesterol efflux restore tumor-associated macrophage phagocytosis and anti-tumor immunity in glioblastoma. Nature Communications (2023).
4. Monoacylglycerol lipase regulates cannabinoid receptor 2-dependent macrophage activation and cancer progression. Nature Communications (2018).
5. Contradictory roles of lipid metabolism in immune response within the tumor microenvironment. Journal of Hematology & Oncology (2021).