Cancer does not merely grow around immune cells; it continually rewires them. A review by J. Noh, J. Lee, C. You and colleagues examines how tumors exploit the intimate relationship between cellular metabolism and epigenetic regulation to reshape innate immune cells inside the tumor microenvironment. The work, published in Experimental & Molecular Medicine, presents metabolic–epigenetic crosstalk as a central mechanism behind immune-cell plasticity—the ability of cells to change their identity and function in response to local conditions.
The tumor microenvironment is a chemically hostile and highly dynamic ecosystem. Rapidly dividing cancer cells consume large quantities of glucose, amino acids and oxygen, while releasing lactate, carbon dioxide, extracellular nucleotides and other metabolites. These changes create regions of hypoxia, acidity and nutrient deprivation. Innate immune cells entering the tumor, including macrophages, neutrophils, dendritic cells and myeloid-derived suppressor cells, must adapt to these conditions. Rather than remaining fixed in a single functional state, they can be pushed toward inflammatory, tissue-remodeling or immunosuppressive programs that may ultimately support tumor survival.
Noh and colleagues emphasize that metabolism is not simply a source of energy for immune cells. Metabolic pathways also generate molecules that directly influence gene regulation. Acetyl-coenzyme A, for example, supplies acetyl groups for histone acetylation, a chromatin modification generally associated with more accessible DNA and active transcription. S-adenosylmethionine provides methyl groups for DNA and histone methylation, while α-ketoglutarate supports enzymes that remove methyl marks from chromatin. In this way, the nutrients and metabolites available to a cell can determine which genes are switched on or silenced.
Other metabolites can exert an opposing influence. Succinate and fumarate, which accumulate when mitochondrial metabolism is altered, can inhibit α-ketoglutarate-dependent dioxygenases, including enzymes involved in DNA and histone demethylation. Their accumulation may therefore stabilize particular epigenetic states. Lactate, long regarded mainly as a waste product of aerobic glycolysis, can also function as a signaling and regulatory molecule. It can affect transcription, chromatin-associated processes and the behavior of neighboring immune cells, helping establish an environment in which immune responses become less effective against malignant tissue.
The review describes hypoxia as another major force connecting metabolism to epigenetic remodeling. Low oxygen activates hypoxia-inducible factors, transcriptional regulators that alter glucose utilization, angiogenesis, survival and inflammatory signaling. Hypoxia can also change the activity of chromatin-modifying enzymes whose reactions depend on oxygen. As a result, oxygen limitation does not merely force immune cells to use alternative fuels; it can leave a lasting molecular imprint on their identity and function. Cells that encounter these signals repeatedly may retain altered transcriptional programs even after local conditions change.
Macrophages provide one of the clearest examples of this plasticity. In tumors, they may acquire features associated with tumor-supportive macrophages, including promotion of blood-vessel formation, extracellular-matrix remodeling and suppression of cytotoxic lymphocytes. These changes are not controlled by a single “on” or “off” switch. Instead, nutrients, oxygen, cytokines and metabolites converge on transcription factors and chromatin regulators. Fatty-acid oxidation, mitochondrial activity, glycolytic flux and amino-acid availability can all influence the epigenetic landscape that determines how macrophages respond to the tumor.
The same principle applies to other innate immune populations. Neutrophils exposed to tumor-derived signals can develop phenotypes that assist invasion, angiogenesis or immune suppression. Dendritic cells may lose efficiency in processing and presenting tumor antigens, weakening the activation of T cells. Myeloid-derived suppressor cells can expand under chronic inflammatory and metabolic stress, consuming nutrients and producing mediators that inhibit antitumor immunity. The review frames these outcomes as interconnected rather than isolated: metabolic competition and epigenetic memory can reinforce one another across several immune-cell types.
This framework has important implications for cancer therapy. Drugs that inhibit histone deacetylases, DNA methyltransferases or specific metabolic enzymes could potentially reprogram immune cells within tumors. Blocking lactate production or transport, altering glutamine metabolism, targeting hypoxia pathways or restoring mitochondrial function may also change the immune landscape. However, the authors’ discussion highlights a major challenge: the same metabolic pathway can have different effects depending on cell type, tumor region and disease stage. A treatment that strengthens antitumor immunity in one setting could impair immune function or damage healthy tissue in another.
Future therapies may therefore need to combine metabolic and epigenetic interventions with immunotherapy rather than targeting either system alone. Careful mapping of metabolites, chromatin states and immune-cell activity at single-cell and spatial resolution could help identify which populations are suppressive, which remain therapeutically recoverable and which metabolic dependencies are unique to the tumor. The review’s central message is that innate immune plasticity is not an accidental consequence of cancer metabolism. It is a dynamic, potentially reversible process in which the tumor’s chemical environment is translated into long-lasting gene-regulatory programs—offering both an explanation for immune failure and a possible route to restore immune attack.
Subject of Research: Metabolic–epigenetic regulation of innate immune cell plasticity in the tumor microenvironment
Article Title: Metabolic–epigenetic crosstalk in innate immune cell plasticity within the tumor microenvironment
Article References: Noh, J., Lee, J., You, C. et al. Metabolic–epigenetic crosstalk in innate immune cell plasticity within the tumor microenvironment. Exp Mol Med (2026). https://doi.org/10.1038/s12276-026-01802-3
Image Credits: AI Generated
DOI: 10.1038/s12276-026-01802-3
Keywords: tumor microenvironment, innate immunity, immune-cell plasticity, cancer metabolism, epigenetics, macrophages, hypoxia, lactate, chromatin remodeling, immunotherapy
