Unveiling the novel value of TREM1 in the proneural-mesenchymal transition of glioma via tumor-associated macrophages

Background Tumor-associated macrophages (TAMs) constitute the most abundant immune cell population in the glioblastoma (GBM) tumor microenvironment. These macrophages critically influence multiple pathological processes in GBM, including recurrence, drug resistance, and immune evasion. However, the role of TREM1 in mediating proneural-to-mesenchymal transition (PMT) in TAMs remains unclear. Methods Single-cell RNA sequencing analysis of 24,366 cells from seven GBM patients identified nine distinct cellular populations, including TAMs and malignant cells. Deconvolution analysis of TCGA mRNA-seq data complemented these findings. Differential expression analysis, weighted gene co-expression network analysis, and LASSO-Cox regression consistently identified TREM1 in TAMs as a PMT-associated biomarker. A co-culture system demonstrated TREM1’s influence on GBM cell malignancy and PMT progression in vitro , while intraperitoneal LP17 administration assessed its impact on tumor growth. Results High TAM infiltration correlated significantly with poor clinical outcomes in GBM patients. Integrated scRNA-seq and mRNA-seq analyses established TREM1 in TAMs as a key PMT biomarker. LP17-mediated TREM1 inhibition attenuated PMT through modulation of the TLR4/PI3K/AKT/mTOR pathway and reduced tumor growth in vivo . Conclusion TREM1 functions as an oncogenic biomarker in TAMs that drives GBM PMT via the TLR4/PI3K/AKT/mTOR axis, with inhibition of TREM1 demonstrating therapeutic potential in both ex vivo and in vivo models.