Tissue Context as a Determinant of Trained Innate Immunity: A Conserved Molecular Toolkit with Divergent Functional Outputs

Abstract Trained innate immunity (TI) challenges the traditional view that adaptive immune cells are solely responsible for establishing immune memory. Instead, innate immune cells can develop a form of memory through persistent epigenetic, metabolic, and antimicrobial modifications, enabling them to respond to secondary challenges in a nonspecific manner. While the molecular mechanisms underlying this trained response have been extensively characterized and are well understood, the intrinsic cellular programs driving trained immunity have not been clearly delineated. Further, the influence of tissue-specific microenvironments remains underexplored. Evidence indicates that the heterogeneity observed in trained immune responses is partly attributable to the functional outcomes shaped by trained immunity within diverse tissue microenvironments, underscoring the complexity and context-dependent nature of this adaptive process. In this review, we explore that TI uses a conserved molecular toolkit whose functional output is dictated by tissue microenvironment. Signals such as oxygen tension, microbiota, local metabolites, cytokine release, and damage-associated molecular patterns can also shape trained innate immunity. The resulting outcomes range from increased antimicrobial defense to maladaptive responses that lead to chronic inflammation and tissue damage. Together, we synthesize findings from hematopoiesis and tissue-resident macrophage biology, emphasizing how immunometabolism and epigenetic mechanisms underpin tissue-specific models of TI. This comprehensive framework resolves contradictions observed across different organs and disease states, positioning tissue instruction as a pivotal determinant of innate immune memory. It demonstrates that trained immunity programs are intricately adapted to tissue niches, with profound implications for infection control, inflammatory diseases, tissue regeneration, and the precise therapeutic targeting of innate immune cells.