Eliminating METTL1‐mediated accumulation of PMN‐MDSCs prevents hepatocellular carcinoma recurrence after radiofrequency ablation

Background and Aims: Radiofrequency ablation (RFA) is an important curative therapy in hepatocellular carcinoma (HCC), but recurrence rate remains as high as all the other HCC therapeutic modalities. Methyltransferase 1 (METTL1), an enzyme for m 7 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). Approach and Results: By immunohistochemistry and multiplex immunofluorescence (mIF) staining, we showed that METTL1 expression was enhanced in post‐RFA recurrent HCC, accompanied by increased CD11b + CD15 + polymorphonuclear‐myeloid–derived suppressor cells (PMN‐MDSCs) and decreased CD8 + T cells. Mechanistically, heat‐mediated METTL1 upregulation enhanced TGF‐β2 translation to form the immunosuppressive environment by induction of myeloid‐derived suppressor cell. Liver‐specific overexpression or knockdown of Mettl1 significantly affected the accumulation of PMN‐MDSCs and subsequently affected CD8 + T cell infiltration. Complete RFA successfully eliminated the tumor, whereas 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. Conclusions: Our study sheds light on the pivotal role of METTL1 in modulating an immunosuppressive microenvironment and demonstrated that interrupting METTL1‐TGF‐β2‐PMN‐MDSC axis could be a therapeutic strategy to restore antitumor immunity and prevent HCC recurrence after RFA treatment, meriting further clinical studies.