Systematic review finds limited direct evidence of macrophage environmental memory

A PRISMA-guided systematic review found that only four of 119 studies directly demonstrated persistent environmental memory in macrophages or monocytes, despite a large body of research describing molecular mechanisms through which these immune cells respond to environmental and tissue-derived stressors. The review searched PubMed and Web of Science through 1 August 2026 and identified candidate mechanisms involving transposable elements, metabolism, epigenetic regulation, non-coding RNAs, extracellular vesicles and systems integration. The central finding is a substantial gap between evidence for environmentally responsive macrophage mechanisms and evidence that those responses persist.

The included studies were assessed 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 studies demonstrated a relevant macrophage or monocyte mechanism without directly establishing persistence or recall, while contextual studies provided broader support. The review used this evidence base to develop the Macrophage Environmental Memory Systems, or MEMS, Framework.

It organizes the literature into six non-mutually-exclusive modules: transposable element regulation, represented in 107 studies; metabolic and signaling reprogramming, in 86; epigenetic regulation, in 33; systems integration, in 17; non-coding RNA regulation, in 14; and extracellular-vesicle-mediated communication, in seven. The overlapping assignments show that the proposed mechanisms are not confined to isolated molecular layers. Transposable element regulation was the most frequently represented module, appearing in 107 of the included studies.

Metabolic and signaling reprogramming was also prominent, with 86 studies assigned to it. Epigenetic regulation appeared in 33 studies, while systems integration, non-coding RNA regulation and extracellular-vesicle-mediated communication appeared in 17, 14 and seven studies, respectively. Together, these counts map the breadth of the literature that may be relevant to acquiring, maintaining, integrating or communicating persistent macrophage states.

The authors present MEMS as an evidence-organizing and hypothesis-generating framework rather than a validated six-component biological pathway. Its purpose is to bring together research that has developed across trained immunity, epigenetic regulation, non-coding RNAs, transposable elements, extracellular vesicles and immunometabolism. The framework does not establish that every module contributes causally to environmental memory, nor does it demonstrate that all six operate together as a single process.

The review also introduces the Macrophage-Mediated Molecular Memory, or M3, hypothesis. This is described as a downstream, experimentally testable extension of MEMS involving the possible communication of environmentally acquired molecular information. It is distinct from the evidence establishing the MEMS Framework itself and remains a hypothesis rather than a demonstrated mechanism.

Future work must determine which mechanisms causally establish and maintain persistent macrophage states. The authors specifically call for exposure-withdrawal studies, longitudinal observations, lineage tracing, perturbational experiments and rechallenge studies. These designs would address the central evidential problem identified by the review: showing not only that macrophages respond to environmental conditions, but that a state persists after the initiating stimulus is removed or that the cells respond differently to a subsequent challenge.

Overall, the systematic review supports the existence of numerous candidate molecular processes that may be relevant to macrophage environmental memory, while finding comparatively little direct evidence of persistence or altered subsequent responses. The MEMS Framework consolidates a scattered literature into six interacting areas for further testing, but the review’s restrictive conclusion is equally important: the biological plausibility of candidate mechanisms has not yet been matched by broad, direct demonstration that macrophages retain an environmental memory.

Subject of Research: Systematic review of molecular evidence for persistent environmental memory in macrophages and monocytes

Article Title: Environmental memory in macrophages: a PRISMA-guided systematic review and the macrophage environmental memory systems framework

Article References: Ruden, D. M. (2026). Environmental memory in macrophages: a PRISMA-guided systematic review and the macrophage environmental memory systems framework. Frontiers in Systems Biology, 6, 1955135. https://doi.org/10.3389/fsysb.2026.1955135

Image Credits: AI Generated

DOI: 10.3389/fsysb.2026.1955135

Keywords: macrophages, environmental memory, monocytes, systematic review, trained immunity, epigenetic regulation, transposable elements, immunometabolism, non-coding RNAs, extracellular vesicles, Environmental, memory