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

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.