Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is a receptor found on macrophages and other immune cells, playing a critical role in immune regulation and inflammation. In the context of Pancreatic Ductal Adenocarcinoma (PDAC), a highly aggressive and treatment-resistant cancer, TREM2 has emerged as a key player in shaping the tumor microenvironment.
Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is a receptor found on macrophages and other immune cells, playing a critical role in immune regulation and inflammation. In the context of Pancreatic Ductal Adenocarcinoma (PDAC), a highly aggressive and treatment-resistant cancer, TREM2 has emerged as a key player in shaping the tumor microenvironment.
The original study by Yang et al. demonstrated that TREM2 deficiency accelerates PDAC progression by promoting the infiltration of proinflammatory macrophages and enhancing IL-1β–mediated inflammation. This inflammatory cascade worsens the tumor’s immunosuppressive environment, allowing cancer cells to evade immune responses and proliferate more aggressively.
Clinical biomarkers like soluble TREM2 (sTREM2) and IL-1β levels could help identify PDAC patients who might benefit from TREM2-targeted therapies. Spatial transcriptomics further offers insights into the spatial relationships between TREM2⁺ macrophages and IL-1β–rich regions, potentially correlating molecular profiles with patient survival outcomes or therapeutic responses.
The gut and tumor microbiome also influence TREM2-driven inflammation, with microbial-derived metabolites such as short-chain fatty acids or lipopolysaccharides potentially modulating TREM2⁺ macrophage phenotypes. This highlights the interplay between microbial ecology and immune regulation in PDAC.
Additionally, TREM2 interacts with other immune and stromal cells, such as cancer-associated fibroblasts (CAFs), T cells, and neutrophils, which collectively shape PDAC’s complex tumor microenvironment. Cytokines like IL-6 and TGF-β secreted by CAFs exacerbate IL-1β–driven inflammation, forming intricate feedback loops that worsen TREM2-deficient tumors.
Future research aims to integrate multiomics approaches (transcriptomics, proteomics, microbiomics) to stratify patients molecularly and develop precision therapies targeting TREM2-related pathways. Understanding TREM2’s multidimensional role could pave the way for biomarker-driven, personalized strategies to combat PDAC effectively.
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