Targeting tumor-intrinsic N7-methylguanosine tRNA modification inhibits MDSC recruitment and improves anti-PD-1 efficacy

We found that PMN-MDSCs level is elevated in the advanced ICCs tissues and is positively associated with the METTL1 and m7G tRNA modification levels. We further showed that impaired m7G tRNA modification impedes the PMN-MDSCs infiltration and inhibits ICC progression. Mechanistically, METTL1-mediated m7G tRNA modification selectively regulates the translation of human CXCL8 and mouse Cxcl5 transcripts, which facilitates the migration of PMN-MDSCs via binding to their cognate receptor CXCR2. Co-blockade of METTL1 and CXCR2 significantly enhances the efficacy of anti-PD-1 treatment in ICC. Taken together, our study reveals the cellular and molecular basis of crosstalk between ICC cells and MDSCs in shaping TIME and affecting ICIs efficacy, which enables reasonable design of new combined therapy targeting dysregulated mRNA translation and suppressive TIME. Overall design: TRAC-Seq was developed to identify the tRNA m7G methylome in mouse intrahepatic cholangiocarcinoma tissues. RNA-seq was used to study the differential translated genes in the Mettl1 knockdown and control human cell lines and mouse cell lines