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

As early as 1931, bacillus Calmette-Guérin (BCG) vaccination was hypothesized to reduce neonatal mortality through nonspecific immune stimulation. The concept of trained immunity was formally proposed in the 21st century, and clinical observations during the COVID-19 pandemic further stimulated interest in the possibility that BCG vaccination might confer broad, non-specific protection against heterologous infections. Trained immunity represents a paradigm-shifting concept in immunology, defining the innate immune system's ability to develop a memory-like state through persistent epigenetic and metabolic reprogramming following initial stimulus exposure. This process enables enhanced, nonspecific responses upon re-exposure, extending immune memory beyond adaptive immunity. The dual role of trained immunity is context-dependent: it is protective in acute infections by improving pathogen clearance, but pathogenic in chronic conditions such as atherosclerosis and certain tumor microenvironments, where sustained proinflammatory memory promotes disease progression. Central mechanisms involve mTOR-HIF-1α signaling, metabolic rewiring of mevalonate/cholesterol pathways, and histone modifications including H3K4me3 and H3K27ac. This review systematically synthesizes the cellular basis, inducing factors, and disease spectrum of trained immunity, providing a conceptual framework for advancing host-directed therapies and precision immunology in infectious, inflammatory, and oncological contexts.