{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T07:46:45Z","timestamp":1791877605917,"version":"4.3.4"},"reference-count":166,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:00:00Z","timestamp":1791849600000},"content-version":"vor","delay-in-days":12,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2022QH372"],"award-info":[{"award-number":["ZR2022QH372"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Triggering receptor expressed on myeloid cells 2 (TREM2) is a pivotal lipid\u2010sensing receptor that governs the functional plasticity and metabolic fitness of mononuclear phagocytes, including microglia, osteoclasts, dendritic cells and tissue\u2010resident macrophages. While originally identified as a genetic risk factor for Alzheimer's disease (AD), TREM2 functions as a context\u2010dependent immunometabolic checkpoint rather than a uniform phenotypic driver, exerting divergent biological outputs dictated by distinct tissue microenvironments and ligand repertoires.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Summary of key contents<\/jats:title>\n                    <jats:p>This review provides a comprehensive synthesis of TREM2 immunobiology, detailing how ligand engagement\u2014including cell\u2010surface phospholipids and apolipoprotein E (ApoE)\u2014activates the DAP12\/DAP10\u2013SYK\u2013PI3K\u2013mTOR signalling axis. This coordinated intracellular cascade instructively drives myeloid adaptation towards metabolically competent disease\u2010associated microglia (DAM) and lipid\u2010associated 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\u2010dependent neuroinflammation. In peripheral inflammatory pathologies such as rheumatoid arthritis and sepsis, TREM2 fine\u2010tunes macrophage efferocytosis and systemic metabolic thresholds. In oncology, TREM2 displays a complex, microenvironment\u2010dependent divergence: in central nervous system malignancies such as glioblastoma (GBM), TREM2 exerts controversial, stage\u2010dependent effects, spanning microglial tumour containment in early stages versus pro\u2010tumoural myelin recycling and immunosuppression by monocyte\u2010derived macrophages in post\u2010treatment recurrence; conversely, in peripheral solid tumours, monocyte\u2010derived TREM2+ tumour\u2010associated macrophages (TAMs) predominantly orchestrate an immunosuppressive, nutrient\u2010deprived niche that impairs cytotoxic T\u2010cell function. Furthermore, we synthesise emerging paradigms along the bidirectional microbiome\u2013gut\u2013brain\u2013tumour axis, elucidating how commensal and intra\u2010tumoural microbial cues dynamically calibrate myeloid signalling tone and therapeutic susceptibility.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>We address translation bottlenecks\u2014including blood\u2013brain barrier (BBB) shuttles, human trial scarcity and soluble TREM2 (sTREM2) biomarker harmonisation\u2014outlining a biomarker\u2010guided, context\u2010tailored precision therapeutic framework for targeting the TREM2 axis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.70863","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T07:01:04Z","timestamp":1791874864000},"source":"Crossref","is-referenced-by-count":0,"title":["Context\u2010dependent TREM2 signalling in myeloid cells: Molecular mechanisms and immunotherapeutic divergence in neurodegeneration and cancer"],"prefix":"10.1002","volume":"16","author":[{"given":"Yaqing","family":"Lv","sequence":"first","affiliation":[{"name":"Department of Operation Room the Affiliated Hospital of Qingdao University  Qingdao Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingpeng","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Operation Room the Affiliated Hospital of Qingdao University  Qingdao Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongfei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery the Affiliated Hospital of Qingdao University  Qingdao Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery the Affiliated Hospital of Qingdao University  Qingdao Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8181-086X","authenticated-orcid":false,"given":"Jiawei","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Radiology the Affiliated Hospital of Qingdao University  Qingdao Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2921-8866","authenticated-orcid":false,"given":"Hai","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery the Affiliated Hospital of Qingdao University  Qingdao Shandong 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