METTL5 Enables Immune Evasion of Liver Cancer via Chemokine mRNA Translation Regulation

The liver microenvironment is essential to immune surveillance and liver cancer progression. Here, the aim is to identify the role of METTL5, the 18S rRNA m⁶A methyltransferase, in regulating the liver immune microenvironment to promote cancer progression. Liver-specific Mettl5 knockout (cKO) in mice exhibits increased immune cell infiltration, especially CD3⁺ and CD4⁺ T cells. Loss of Mettl5 inhibits intrahepatic cholangiocarcinoma (ICC) progression. By scRNA-seq analysis, it is found that ICC from both cKO mice and human METTL5 low expression group correlates with increased CD8⁺ T cells but decreased macrophages, which is associated with better survival. Adoptive transfer of macrophages significantly promotes ICC progression. scRNA-seq and scTCR-seq analysis show that cKO mice exhibit reduced immunosuppressive Ms4a7⁺C1qa⁺ tumor-associated macrophages (TAMs) but increased intratumoral IFN-γ⁺CD8⁺ T cell infiltration and expansion. Mechanistically, METTL5-mediated 18S rRNA m⁶A modification downregulates the mRNA translation of CXCL16 to exclude CD8⁺ T cells. Knockout of Mettl5 significantly increases CD8⁺ T cell infiltration in vivo. Combined METTL5 targeting using lipid nanoparticle-encapsulated siRNA and PD-1 blockade provokes anti-tumor immunity to eradicate ICC tumors. Additionally, METTL5^Low human ICC correlates with responsiveness to immunotherapy. The study highlights the strong immuno-evasive ability of METTL5 as a promising therapeutic target in ICC.