| HRA006821
(Open Access)
|
In this study, we unravel that METTL5, the 18S rRNA m6A methytransferase, promotes ICC progression via reshaping ICC tumor immune microenvironment. Biologically, liver-specific Mettl5 knockout (cKO) mice exhibited decreased ICC tumor burden compared to control mice, accompanied with increased anti-tumor IFN-y+CD8+T cells and decreased infiltration of tumor-associated macrophages (TAMs) via single cell RNA sequencing (scRNAseq) analysis. Mechanistically, METTL5-mediated 18S rRNA m6A modification regulated the mRNA translation of chemokines that recruited CD8+T cells and TAMs, respectively. In human ICC, we validated that low METTL5 expression correlated with increased tumor anti-tumoral CD8+T cells and decreased pro-tumoral TAMs. Ultimately, targeting METTL5 using lipid nanoparticle encapsulated siRNA combined with anti-PD-1 therapy significantly provoked anti-tumor immunity and mitigated ICC progression in ICC mouse model, suggesting METTL5 as a promising therapeutic target for treating ICC. |
