Molecular and cellular bases of trained immunity

Innate immune cells can adopt long-lasting functional states following transient stimulation. This process of trained immunity was initially defined in monocytes but occurs in multiple cellular systems, including tissue-resident macrophages and hematopoietic stem and progenitor cells. Trained immunity is mediated through coordinated epigenetic and metabolic alterations that enhance secondary inflammatory responses. In this review, we highlight shared principles across systems while emphasizing how developmental and tissue contexts shape trained immunity. We propose a unifying framework in which metabolic and epigenetic remodeling initiate trained states, but persisting components, such as transcription factor activity and environmental signals, are required for durable maintenance. Understanding how trained immunity is encoded, preserved, and regulated is essential for harnessing its potential in infection, inflammation, and immunotherapy.