Innate Immune Memory: How Epigenetic and Metabolic Rewiring Shapes Health and Disease

For most of the twentieth century, immunologists drew a sharp line between the two arms of the immune system. Adaptive immunity, carried by T and B lymphocytes, was thought to be the sole keeper of immunological memory, while the innate immune system was viewed as a rapid but amnesiac first responder. That tidy division has now collapsed. A comprehensive review published in the Journal of Molecular Medicine synthesizes the evidence behind trained immunity, the paradigm-shifting concept that innate immune cells can acquire a memory-like state through persistent epigenetic and metabolic reprogramming, and maps how this phenomenon cuts both ways in human disease: protective during acute infections, yet potentially harmful in chronic inflammatory and oncological settings.

The intellectual roots of the idea reach back further than most readers might expect. As early as 1931, researchers hypothesized that bacillus Calmette–Guérin (BCG) vaccination could reduce neonatal mortality through nonspecific stimulation of the immune system, an effect that could not be explained by protection against tuberculosis alone. The concept of trained immunity was formally articulated in the twenty-first century, when studies showed that monocytes exposed to certain microbial components responded more vigorously to a second, unrelated challenge. Interest surged again during the COVID-19 pandemic, when clinical observations revived the question of whether BCG vaccination might confer broad, heterologous protection against viral infections. The new review, led by Liqi Liao, Yong-Xian Cheng and Xuhan Liu, places these threads into a single conceptual framework spanning cellular basis, inducing factors and the full disease spectrum.

At the cellular level, trained immunity is not confined to circulating monocytes and macrophages. The review emphasizes that hematopoietic stem and progenitor cells in the bone marrow can themselves be trained, generating myeloid progeny with an enhanced inflammatory repertoire long after the initial stimulus has cleared. BCG vaccination in humans has been shown to reprogram the hematopoietic progenitor compartment, and animal studies demonstrate that trained hematopoietic stem cells generate protective innate immunity against tuberculosis. Tissue-resident macrophages, natural killer cells, innate lymphoid-like cells and dendritic cells have all been shown to display memory-like behavior under appropriate stimulation. Even organisms lacking adaptive immunity, from invertebrates to plants, exhibit forms of innate immune memory, suggesting that this is an ancient defense strategy rather than a mammalian novelty.

The triggers of trained immunity are diverse. Pathogen-associated molecular patterns such as β-glucan from fungal cell walls and lipopolysaccharide from bacterial membranes can induce the trained state, as can damage-associated molecular patterns released by injured tissue. Oxidized low-density lipoproteins, oxidized phospholipids carried on lipoprotein(a), and even catecholamines released during stress have been shown to train monocytes toward a proinflammatory phenotype. The Western diet, rich in fat and sugar, triggers NLRP3-dependent innate immune reprogramming, effectively training the immune system toward chronic metaflammation. This breadth of inducers explains why trained immunity is now implicated far beyond infectious disease, in atherosclerosis, metabolic syndrome and cancer.

Mechanistically, the review centers on what its authors call the epigenetic-metabolic axis. Upon stimulation, innate immune cells activate the mTOR–HIF-1α signaling cascade, driving a shift from oxidative phosphorylation toward aerobic glycolysis, a metabolic signature once considered exclusive to cancer cells. This metabolic rewiring is not merely fuel for the cell; it directly shapes the epigenetic landscape. Accumulated glycolytic intermediates and altered flux through the tricarboxylic acid cycle influence the availability of substrates and cofactors for chromatin-modifying enzymes, linking cellular energetics to gene regulation in a feedback loop that can persist for weeks to months.

Two histone modifications emerge as central players. Trimethylation of histone H3 at lysine 4 (H3K4me3) and acetylation at lysine 27 (H3K27ac) mark promoters and enhancers of inflammatory genes, keeping them in a poised state that allows rapid transcription upon re-exposure to a stimulus. The mevalonate and cholesterol biosynthesis pathways provide a second metabolic route into this program: activation of these pathways in trained monocytes drives both histone modifications and long-term functional changes. One-carbon metabolism, which supplies S-adenosylmethionine for methylation reactions, and NAD+-dependent sirtuins further couple metabolic state to chromatin structure. Long noncoding RNAs positioned near immune genes and three-dimensional chromatin architecture, including topologically associated domains, add additional layers of regulation that keep trained cells ready for action.

The protective face of trained immunity is best illustrated by BCG. Vaccination induces NOD2-dependent epigenetic reprogramming of monocytes, producing enhanced cytokine responses to unrelated pathogens. Randomized trials, including the ACTIVATE study in elderly individuals, showed that BCG vaccination increased the time to first infection, and experimental challenge studies demonstrated reduced viremia after yellow fever vaccination in BCG-vaccinated volunteers. Animal work extends the principle: intravenous BCG protects mice against lethal SARS-CoV-2 challenge, mucosal BCG and MTBVAC vaccination induce stronger trained immunity than standard intradermal routes, and trained alveolar macrophages in the lung confer prolonged antibacterial and antitumor protection. β-glucan-induced trained immunity has been shown to protect against Leishmania infection and to promote antitumor granulopoiesis, while trained macrophages can even confer heterologous protection against gram-negative bacteria after Staphylococcus aureus exposure.

Yet the same machinery can turn against the host. In atherosclerosis, oxidized low-density lipoprotein trains monocytes and macrophages to produce sustained proinflammatory cytokines and form foam cells, embedding a proinflammatory memory in the arterial wall. Myocardial infarction itself drives trained immunity of monocytes, accelerating subsequent atherosclerosis, and maladaptive training of myelopoiesis has been shown to link inflammatory comorbidities. In certain tumor microenvironments, trained or lipid-associated macrophages facilitate cancer progression rather than restraint. Chronic interleukin-1 exposure pushes hematopoietic stem cells toward precocious myeloid differentiation at the expense of self-renewal, a shift that can undermine long-term immune resilience. The review stresses that the outcome of trained immunity is strictly context-dependent: the identical epigenetic-metabolic program that accelerates pathogen clearance in acute infection can fuel disease progression when the stimulus is chronic.

This duality opens a therapeutic frontier. Host-directed therapies could deliberately induce trained immunity to boost vaccine efficacy or enhance antimicrobial defense, using agents such as β-glucan particles, bacterial outer membrane vesicles, or nanobiologics that deliver trained-immunity-promoting signals. Conversely, dampening pathological training could treat cardiovascular disease, with the mevalonate pathway, mTOR signaling and specific histone-modifying enzymes such as lysine methyltransferases and demethylases serving as druggable nodes. In oncology, strategies that retrain pro-metastatic macrophages or combine trained-immunity-inducing nanoparticles with checkpoint inhibitors have already shown promise in preclinical models. Compounds such as oroxylin A, which promotes LC3-associated phagocytosis in trained macrophages, hint at pharmacological routes to harness the process.

The authors argue that single-cell RNA sequencing, multi-omics profiling and systems approaches will be essential to translate these insights into precision immunology, identifying which patients stand to benefit from immune training and which are at risk from it. Recent multi-omics work on BCG vaccination has already revealed epigenetic cell states that predict the strength of the trained response in individuals, a first step toward personalized vaccination strategies. As the field matures, trained immunity is shifting from a provocative concept to a practical framework: one that reframes immune memory as a continuum spanning innate and adaptive systems, and one whose manipulation, the review concludes, could reshape the prevention and treatment of infectious, inflammatory and oncological disease alike.

Subject of Research: The epigenetic and metabolic mechanisms of trained immunity and their dual roles in infection, chronic inflammation and cancer

Article Title: The epigenetic-metabolic axis of trained immunity: dual roles in disease pathogenesis and intervention

Article References: The epigenetic-metabolic axis of trained immunity: dual roles in disease pathogenesis and intervention. (n.d.). https://doi.org/10.1007/s00109-026-02729-y

Image Credits: AI Generated

DOI: 10.1007/s00109-026-02729-y

Keywords: trained immunity, epigenetic reprogramming, metabolic rewiring, BCG vaccine, innate immune memory, mTOR-HIF-1α signaling, histone modification, mevalonate pathway, atherosclerosis, cancer immunotherapy, monocytes, hematopoietic stem cells