TREM2 mediates macrophage suppression of NLRP3 inflammasome pathway to promote non-small cell lung cancer progression.

Non-small cell lung cancer (NSCLC) represents the predominant form of lung cancer, comprising around 80%-85% of all cases. The Triggering Receptor Expressed on Myeloid Cells 2(TREM2) plays a role in reducing inflammation by influencing the polarization of M2 macrophages. This research aims to explore how TREM2 + macrophages modulate NLRP3 signaling pathway to influence tumor development in NSCLC. In TREM2 knockdown macrophages, the expression levels of NLRP3 at both mRNA and protein levels are significantly increased, which accelerates the cleavage of the downstream signaling molecule Caspase-1 and the release of IL-1β, While diminishing the growth and invasive potential of NSCLC cells. In TREM2-deficient macrophages, treatment with the NLRP3 inflammasome-specific inhibitor MCC950 reverses Caspase-1 cleavage and IL-1β release, thereby restoring the growth and invasive capacity of NSCLC cells. Elevated levels of sTREM2 and IL-1β were detected in the peripheral blood of NSCLC patients. The immunohistochemical staining results also showed that the expression level of TREM2 in the lung cancer tissues of NSCLC patients tended to increase compared to the adjacent normal tissues. Despite numerous studies on TREM2 in neurodegenerative diseases and immune regulation, its specific role within the tumor microenvironment of non-small cell lung cancer (NSCLC) and its relationship with the inflammasome pathway have been infrequently reported. This study elucidates the mechanism by which TREM2 inhibits NLRP3 inflammasome activity in NSCLC, thereby promoting tumor immune evasion and progression. Therefore, TREM2 could serve as a promising target for therapeutic interventions in NSCLC treatment.