TREM2 (Triggering Receptor Expressed On Myeloid Cells 2)

Aggressive LDL lowering reverses inflammasome activation and induces pro-resolving changes in macrophages in Jak2VF MPN, halting atherosclerosis progression and promoting features of plaque stabilization. These findings suggest that aggressive LDL cholesterol lowering could reverse atherosclerotic cardiovascular disease (ACVD) risk in individuals with JAK2VF CHIP or MPN.

This contrasts sharply with its metabolic role in benign prostatic hyperplasia and its protective role in non-malignant renal injury. We also consider the translational potential of TREM2 as a prognostic biomarker (specifically urine detection) and as a therapeutic target to reverse immunotherapy resistance.

Genetic ablation of Trem2 or pharmacologic targeting with antisense oligonucleotides suppress paclitaxel-induced breast cancer lung metastasis in vivo. Collectively, our findings demonstrate that paclitaxel, but not nab-paclitaxel, stimulates TREM2 expression and expands TREM2+ macrophages, suggesting that TREM2 targeting could enhance paclitaxel efficacy while limiting metastasis.

These effects of Cyst-C are abolished by a cell-type-specific deletion (Cx3cr1TREM2-/-) or mutation of TREM2 (TREM2R47H) or Cyst-C (Cyst-CL68Q) in microglia. Together, these findings provide significant conceptual advances into cancer neuroscience and establish therapeutic avenues that are distinct from the present amyloid-lowering strategies, aiming at degrading the existing amyloid plaques for precision-targeted AD therapy.

Tumor clearance depends, in part, on FAS expression on cancer cells, revealing an IL-12-FAS axis for IL-12-armored CAR-T activity. These findings position IL-12-producing, myeloid-directed CAR-T as a broad strategy to remodel the TME and drive anti-tumor immunity for solid cancers.

Notably, the clinical agonist sotigalimab similarly enhances human CD8+ T cell migration in vitro. Our findings highlight the significance of combining GPC3-CAR-T therapy with CD40 agonist as a critical pre-requisite for eliciting reeducation of TAMs and enhancing the efficacy of CAR-T therapy in HCC.

The results of our study indicate that DKMX extracts exert their anti-neuroinflammatory effects primarily through the TREM2/Wnt/β-catenin pathway, thereby alleviating symptoms and enhancing functional outcomes in rats with PSD.

Our pilot study demonstrated the feasibility of generating high-quality, large-scale single-cell multi-omic data from the human amygdala. We observed abundant AD-associated microglia in amygdala, suggesting the possibility that the regional vulnerability of amygdala to multiple neurodegenerative disorders might be in part due to different glial composition.

TREM2 positively regulates DAP12 and forms a complex that impacts glioma development via the PI3K/AKT pathway. Targeting the TREM2/DAP12 complex presents a potential therapeutic approach for gliomas.

This study novelly suggests ZEB2 as a transcription factor that promotes TREM2 expression. Further investigation into the role of ZEB2 in various TREM2-associated diseases is warranted.

Moreover, the mechanistic study indicated that overexpression of TREM2 modulated microglial M2 polarization and promoted the proliferation and differentiation of NSCs partly via the PI3K/Akt and ERK1/2 signaling pathways. Collectively, these findings revealed that TREM2 may modulate microglial M2 polarization to inhibit neuroinflammation and increase the M2 microglia-derived BDNF to rescue hippocampal neurogenesis in ApoE-/- mice, and TREM2 can be considered a promising therapeutic factor to promote neurogenesis in AD and other brain diseases.

This review synthesizes current knowledge of the molecular mechanisms underlying TREM2 signaling in myeloid cells, its influence on TME remodeling, and its potential as both a biomarker and therapeutic target in cancer immunotherapy. Finally, we highlight current challenges and future perspectives in harnessing TREM2-directed strategies to counteract tumor immune evasion.