TUMOR INTRINSIC METTL5 EXPRESSION DRIVES IMMUNE EVASION TO PROMOTE INTRAHEPATIC CHOLANGIOCARCINOMA PROGRESSION

Intrahepatic cholangiocarcinoma (ICC) is an aggressive and heterogeneous malignancy derived from biliary tract in liver, with increasing incidence and mortality rates worldwide, dismal prognosis and limited treatment options. Novel effective therapeutic strategies are urgently needed. Here, we unravel that METTL5 as the 18S rRNA m⁶A methytransferase, promotes ICC progression via reshaping ICC tumor immune microenvironment. Liver-specific Mettl5 knockout (cKO) mice exhibited decreased ICC tumor burden compared to control mice. Single cell RNA sequencing (scRNAseq) analysis showed that anti-tumor IFN-γ⁺CD8⁺T cells were remarkably increased in cKO mice, accompanied by decreased infiltration of tumor-associated macrophages (TAMs) compared to control mice. 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 by scRNAseq and bulk RNA sequencing. Targeting METTL5 using lipid nanoparticle encapsulated siRNA combined with anti-PD-1 therapy significantly provoked anti-tumor immunity and mitigated ICC progression in mouse ICC model. Our study uncovers that METTL5 is a novel and promising therapeutic target in treating ICC.