Metabolic–epigenetic crosstalk in innate immune cell plasticity within the tumor microenvironment

Abstract

The tumor microenvironment exerts profound metabolic and epigenetic pressures that shape the plasticity of innate immune cells, influencing their capacity to promote or suppress tumor progression. Emerging evidence highlights the intricate interplay between metabolic reprogramming and epigenetic modifications in macrophages, neutrophils, and other innate immune populations within the tumor microenvironment. Tumor-derived metabolites, hypoxia, and nutrient availability dynamically regulate chromatin accessibility, histone modifications, and DNA methylation patterns, thereby driving context-dependent immune phenotypes. Notably, metabolic rewiring can imprint long-lasting epigenetic changes, a phenomenon known as innate immune memory, which alters subsequent immune responses. Here, we discuss how key metabolic pathways, including glycolysis, fatty acid oxidation, and amino acid metabolism, govern innate immune cell fate and function via epigenetic mechanisms. We also highlight recent advances in epigenomic profiling that have unveiled distinct chromatin landscapes associated with innate immune dysfunction across cancer types. Finally, we explore emerging therapeutic strategies that target the metabolic–epigenetic axis to restore innate immune surveillance and enhance immunotherapy efficacy. A deeper understanding of this metabolic–epigenetic crosstalk could reveal novel avenues for modulating innate immunity in cancer therapy. Cancer is increasingly viewed as a dynamic ecosystem shaped by interactions between malignant cells and the tumor microenvironment. This Review examines how metabolic and epigenetic pressures within the tumor microenvironment regulate the plasticity of innate immune cells, including macrophages, neutrophils, and other innate immune populations. Tumor-derived metabolites, hypoxia, and nutrient availability modulate chromatin accessibility, histone modifications, and DNA methylation, thereby driving context-dependent immune phenotypes that either support or suppress tumor progression. The authors discuss how glycolysis, fatty acid oxidation, and amino acid metabolism govern innate immune cell fate through epigenetic mechanisms, including long-lasting imprints associated with innate immune memory. Recent epigenomic profiling is also highlighted for revealing chromatin landscapes linked to innate immune dysfunction across cancer types, supporting therapeutic targeting of the metabolic–epigenetic axis in cancer immunotherapy. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the authors.