Context‐dependent TREM2 signalling in myeloid cells: Molecular mechanisms and immunotherapeutic divergence in neurodegeneration and cancer
- 1the Affiliated Hospital of Qingdao University
Abstract
Background Triggering receptor expressed on myeloid cells 2 (TREM2) is a pivotal lipid‐sensing receptor that governs the functional plasticity and metabolic fitness of mononuclear phagocytes, including microglia, osteoclasts, dendritic cells and tissue‐resident macrophages. While originally identified as a genetic risk factor for Alzheimer's disease (AD), TREM2 functions as a context‐dependent immunometabolic checkpoint rather than a uniform phenotypic driver, exerting divergent biological outputs dictated by distinct tissue microenvironments and ligand repertoires. Summary of key contents This review provides a comprehensive synthesis of TREM2 immunobiology, detailing how ligand engagement—including cell‐surface phospholipids and apolipoprotein E (ApoE)—activates the DAP12/DAP10–SYK–PI3K–mTOR signalling axis. This coordinated intracellular cascade instructively drives myeloid adaptation towards metabolically competent disease‐associated microglia (DAM) and lipid‐associated macrophage (LAM) states, sustaining bioenergetics and debris clearance under pathological stress. Across neurodegenerative proteinopathies and acute cerebral ischemia, TREM2 signalling is predominantly neuroprotective by promoting aggregate compaction and mitigating secondary excitotoxicity, although chronic dysregulated activation may drive stage‐dependent neuroinflammation. In peripheral inflammatory pathologies such as rheumatoid arthritis and sepsis, TREM2 fine‐tunes macrophage efferocytosis and systemic metabolic thresholds. In oncology, TREM2 displays a complex, microenvironment‐dependent divergence: in central nervous system malignancies such as glioblastoma (GBM), TREM2 exerts controversial, stage‐dependent effects, spanning microglial tumour containment in early stages versus pro‐tumoural myelin recycling and immunosuppression by monocyte‐derived macrophages in post‐treatment recurrence; conversely, in peripheral solid tumours, monocyte‐derived TREM2+ tumour‐associated macrophages (TAMs) predominantly orchestrate an immunosuppressive, nutrient‐deprived niche that impairs cytotoxic T‐cell function. Furthermore, we synthesise emerging paradigms along the bidirectional microbiome–gut–brain–tumour axis, elucidating how commensal and intra‐tumoural microbial cues dynamically calibrate myeloid signalling tone and therapeutic susceptibility. Conclusion We address translation bottlenecks—including blood–brain barrier (BBB) shuttles, human trial scarcity and soluble TREM2 (sTREM2) biomarker harmonisation—outlining a biomarker‐guided, context‐tailored precision therapeutic framework for targeting the TREM2 axis.
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BibTeX
@article{lv2026contextdependent,
title = {{Context‐dependent TREM2 signalling in myeloid cells: Molecular mechanisms and immunotherapeutic divergence in neurodegeneration and cancer}},
author = {Yaqing Lv and Mingpeng Shi and Yongfei Zhao and Yi Yu and Jiawei Lv and Hai Zhao},
journal = {Clinical and translational medicine},
year = {2026},
month = oct,
doi = {10.1002/ctm2.70863},
url = {https://europepmc.org/article/PMC/PMC13659281},
note = {CC BY},
}
RIS
TY - JOUR
TI - Context‐dependent TREM2 signalling in myeloid cells: Molecular mechanisms and immunotherapeutic divergence in neurodegeneration and cancer
AU - Yaqing Lv
AU - Mingpeng Shi
AU - Yongfei Zhao
AU - Yi Yu
AU - Jiawei Lv
AU - Hai Zhao
PY - 2026
DA - 2026/10/01
JO - Clinical and translational medicine
DO - 10.1002/ctm2.70863
UR - https://europepmc.org/article/PMC/PMC13659281
AB - Background Triggering receptor expressed on myeloid cells 2 (TREM2) is a pivotal lipid‐sensing receptor that governs the functional plasticity and metabolic fitness of mononuclear phagocytes, including microglia, osteoclasts, dendritic cells and tissue‐resident macrophages. While originally identified as a genetic risk factor for Alzheimer's disease (AD), TREM2 functions as a context‐dependent immunometabolic checkpoint rather than a uniform phenotypic driver, exerting divergent biological outputs dictated by distinct tissue microenvironments and ligand repertoires. Summary of key contents This review provides a comprehensive synthesis of TREM2 immunobiology, detailing how ligand engagement—including cell‐surface phospholipids and apolipoprotein E (ApoE)—activates the DAP12/DAP10–SYK–PI3K–mTOR signalling axis. This coordinated intracellular cascade instructively drives myeloid adaptation towards metabolically competent disease‐associated microglia (DAM) and lipid‐associated macrophage (LAM) states, sustaining bioenergetics and debris clearance under pathological stress. Across neurodegenerative proteinopathies and acute cerebral ischemia, TREM2 signalling is predominantly neuroprotective by promoting aggregate compaction and mitigating secondary excitotoxicity, although chronic dysregulated activation may drive stage‐dependent neuroinflammation. In peripheral inflammatory pathologies such as rheumatoid arthritis and sepsis, TREM2 fine‐tunes macrophage efferocytosis and systemic metabolic thresholds. In oncology, TREM2 displays a complex, microenvironment‐dependent divergence: in central nervous system malignancies such as glioblastoma (GBM), TREM2 exerts controversial, stage‐dependent effects, spanning microglial tumour containment in early stages versus pro‐tumoural myelin recycling and immunosuppression by monocyte‐derived macrophages in post‐treatment recurrence; conversely, in peripheral solid tumours, monocyte‐derived TREM2+ tumour‐associated macrophages (TAMs) predominantly orchestrate an immunosuppressive, nutrient‐deprived niche that impairs cytotoxic T‐cell function. Furthermore, we synthesise emerging paradigms along the bidirectional microbiome–gut–brain–tumour axis, elucidating how commensal and intra‐tumoural microbial cues dynamically calibrate myeloid signalling tone and therapeutic susceptibility. Conclusion We address translation bottlenecks—including blood–brain barrier (BBB) shuttles, human trial scarcity and soluble TREM2 (sTREM2) biomarker harmonisation—outlining a biomarker‐guided, context‐tailored precision therapeutic framework for targeting the TREM2 axis.
SN - 2001-1326
ER -