Front Syst Biol. 2026 ;6
1955135
Background: Macrophages respond dynamically to environmental and tissue-derived stressors, but the extent to which these responses constitute persistent environmental memory remains unclear. Studies of trained immunity, epigenetic regulation, non-coding RNAs, transposable elements, extracellular vesicles (EVs), and immunometabolism suggest multiple mechanisms that may contribute to persistent macrophage states, yet these fields have largely developed independently. We therefore systematically evaluated evidence for macrophage environmental memory and used the resulting evidence base to develop the Macrophage Environmental Memory Systems (MEMS) Framework.
Methods: A PRISMA-guided systematic review of PubMed and Web of Science was completed on 1 August 2026. Searches identified 1,405 records; after removal of 404 duplicates, 1,001 unique records underwent screening. Following title/abstract screening and final evidence audit, 119 primary studies were included. Studies were classified as Direct when a prior stressor induced a macrophage or monocyte molecular or functional state that persisted after removal of the initiating stimulus, was maintained over time or through cell division, or altered the response to a subsequent challenge; Mechanistic when they demonstrated a relevant macrophage or monocyte mechanism without directly establishing persistence or recall; or Contextual when they provided broader mechanistic support. Studies were assigned to six non-mutually exclusive MEMS modules.
Results: Of the 119 included studies, only 4 met the stringent criteria for Direct evidence, whereas 50 were Mechanistic and 65 Contextual, revealing a substantial gap between the extensive literature describing environmentally responsive macrophage mechanisms and evidence directly demonstrating persistent environmental memory. Module assignments overlapped and included transposable element regulation (n = 107), metabolic and signaling reprogramming (n = 86), epigenetic regulation (n = 33), systems integration (n = 17), non-coding RNA regulation (n = 14), and EV-mediated communication (n = 7). The evidence therefore identifies numerous candidate mechanisms that may contribute to the acquisition, maintenance, integration, or communication of persistent macrophage states, while demonstrating that direct evidence of persistence remains limited.
Conclusion: The available literature provides broad mechanistic support for biological processes potentially relevant to macrophage environmental memory but comparatively little direct evidence of persistence or altered subsequent responses. The resulting MEMS Framework organizes this heterogeneous evidence into six interacting molecular systems and is proposed as an evidence-organizing and hypothesis-generating framework rather than a validated six-component biological pathway. Prospective exposure-withdrawal, longitudinal, lineage-tracing, perturbational, and rechallenge studies are needed to determine which mechanisms causally establish and maintain persistent macrophage states. The Macrophage-Mediated Molecular Memory (M3) hypothesis represents a downstream, experimentally testable extension of MEMS involving potential communication of environmentally acquired molecular information and remains distinct from evidence establishing the MEMS Framework itself.
Keywords: MEMS; environmental memory; epigenetics; extracellular vesicles; immunometabolism; macrophages; non-coding RNA; systems immunology