Radiofrequency ablation (RFA) is an important curative therapy in hepatocellular carcinoma (HCC), but recurrence rate remains high as all the other HCC therapeutic modalities. Methyltransferase 1 (METTL1), an enzyme for m G tRNA modification, was reported to promote HCC development. Here, we assessed the role of METTL1 in shaping the immunosuppressive tumor microenvironment after insufficient RFA (iRFA).
By IHC and multiplex immunofluorescence (mIF) staining, we showed that METTL1 expression was enhanced in post-RFA recurrent HCC, accompanied by increased CD11b CD15 PMN-MDSCs and decreased CD8 T cells. Mechanistically, heat-mediated METTL1 upregulation enhanced TGF-β2 translation to form the immunosuppressive environment by induction of MDSC. Liver specific overexpression or knockout of Mettl1 significantly affected the accumulation of PMN-MDSCs and subsequently affected CD8 T cell infiltration. Complete RFA (cRFA) successfully eliminated the tumor, while iRFA-treated mice exhibited enhanced tumor growth and metastasis with increased PMN-MDSC accumulation and decreased CD8 T cells compared to sham surgery. Interrupting METTL1-TGF-β2-PMN-MDSC axis by anti-Ly6G antibody, or knockdown of hepatoma-intrinsic Mettl1 or Tgfb2, or TGF-β signaling blockade significantly mitigated tumor progression induced by iRFA and restored CD8 T cell population.
Our study sheds light on a previsouly unrevealed role of METTL1 in modulating an immunosuppressive microenvironment, and demonstrated that interrupting METTL1- TGF-β2-PMN-MDSC axis could be a novel therapeutic strategy to restore anti-tumor immunity and prevent HCC recurrence after RFA treatment, meriting further clinical studies.

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