YTHDF1 promotes NASH‐HCC tumorigenesis via EZH2‐IL‐6 signaling, which recruits and activates MDSCs to cause cytotoxic CD8+ T‐cell dysfunction. LNP‐siYthdf1 markedly decreased YTHDF1 protein levels in mouse NASH‐HCC tumors. LNP‐siYthdf1 combined with anti‐PD‐1 synergistically decreased tumor burden and cell proliferation, which means LNP‐siYthdf1 has potential in anti‐PD‐1 therapy in NASH‐HCC. Here, EZH2 is linked to hepatocellular carcinoma.