Epigenetic and Metabolic Changes That Drive Trained Immunity in Response to Microbes and Vaccines

Trained immunity is a form of innate immune memory in which initial exposure to microbial components or vaccines leads to long-lasting functional reprogramming of innate immune cells through epigenetic and metabolic changes. Unlike adaptive immunity, it does not rely on B or T lymphocytes and provides broad, nonspecific protection against various pathogens. This phenomenon has been observed across a range of immune cells, including monocytes, macrophages, neutrophils, NK cells and even γδ T-cells, as well as at the level of haematopoietic stem and progenitor cells (HSPCs). Key inducers include microbial products (e.g., β-glucan, BCG and MMR vaccines), metabolic byproducts (e.g., mevalonate and lactate) and cytokines such as IL-1β. These agents activate signalling pathways such as the Akt/mTOR/HIF-1α pathway and lead to chromatin remodelling via histone modifications such as H3K4me3 and H3K9me3. Immunometabolism plays a pivotal role, with trained cells shifting toward glycolysis, glutaminolysis and cholesterol synthesis. Lactate and fumarate further link metabolism to epigenetic remodelling. Notably, trained immunity can be protective in infectious diseases and beneficial in noninfectious contexts, such as cancer immunotherapy and autoimmune regulation. This review provides a comprehensive overview of the cellular, epigenetic and metabolic mechanisms underlying trained immunity, highlighting how innate immune cells acquire memory-like properties independent of adaptive immunity. This study also provides insights into the therapeutic potential of leveraging trained immunity for vaccine development, infection control and immunomodulation in noninfectious diseases.