Trem1 sustains liver cancer stemness in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and a leading cause of cancer-related mortality worldwide. Although the Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) is well known for shaping tumor-infiltrating myeloid populations and promoting an immunosuppressive tumor microenvironment, its tumor-intrinsic function remains poorly defined. Here, we identify a previously unknown function of TREM1 in sustaining the stem-like properties of liver cancer stem-like cells (LCSLCs). Flow cytometric analyses revealed high TREM1 expression within the CD133⁺EpCAM⁺ LCSLC population. CRISPR-Cas9-mediated knockout of TREM1 in HCC cell lines markedly impaired proliferation and migration while enhancing apoptosis. Specifically, in LCSLCs TREM1 deficiency reduced clonogenic growth and spheroid formation, indicating loss of self-renewal and stemness. Consistently, cell line-derived xenografts generated from TREM1-deficient LCSLCs exhibited substantially diminished tumorigenicity in vivo. Transcriptomic profiling of FACS purified LCSLCs demonstrated that TREM1 loss disrupted various nuclear and extracellular signaling programs associated with oncogenic and stemness pathways. Moreover, pharmacologic inhibition of TREM1 using the small-molecule antagonist VJDT phenocopied the tumor-suppressive effects observed in genetic knockout models. Collectively, these findings establish TREM1 as a critical intrinsic regulator of LCSLC survival and tumorigenic potential, independent of its immunomodulatory activity in the tumor microenvironment. Therapeutically, targeting TREM1 may offer a dual-action approach to simultaneously suppress cancer stem-like cell function and attenuate cancer progression in HCC.