Revisiting TREM2: from multi-omics signaling networks to clinical translation

TREM2 is a cell surface receptor that plays a crucial role in regulating immune responses, particularly in myeloid cells such as macrophages, dendritic cells, and microglia. Initially studied for its involvement in neuroinflammation and neurodegenerative diseases, while recent evidence has highlighted its broader implications in cancer and various other diseases. Recent studies show that TREM2 plays an immunoprotective role prompted by central nervous system-enriched sphingolipids during GBM progression. TREM2 overexpression represses GBM and synergizes with anti-PD-1 therapy, suggesting a potential therapeutic avenue in cancer immunotherapy. This review provides a comprehensive overview of TREM2 biology, focusing on its molecular structure, signaling pathways, and functional roles in different disease contexts. In Alzheimer's disease, TREM2 mutations are associated with altered immune responses and impaired amyloid-beta clearance, suggesting a potential therapeutic target. In cancer, TREM2 contributes to immune evasion, tumor progression, and metastasis, with emerging strategies aiming to target TREM2 to enhance anti-tumor immunity. Additionally, TREM2 is implicated in a range of other conditions, including autoimmune diseases, multiple sclerosis, and Parkinson's disease, where it may regulate inflammatory responses and tissue damage. Despite promising findings, several challenges remain in understanding TREM2's complex role across diverse diseases. Future research directions include unraveling its precise mechanisms, validating its therapeutic potential, and exploring clinical interventions targeting TREM2. This review provides a comprehensive overview of TREM2 biology, synthesizing insights from recent single-cell transcriptomics and metabolic profiling. We focus on its molecular structure, complex signaling networks, and context-dependent functional roles across diverse disease landscapes.