Using syngeneic transplantation models and human clinical samples, we clarify that ACVR2A-deficient HCC cells produce and secrete lactate via the upregulation of lactate dehydrogenase A (LDHA) and monocarboxylate transporter 4 (MCT4) expression levels, which promotes regulatory T (Treg) cell accumulation and then acquires resistance to immune checkpoint inhibitors. This evidence concerns the gene ACVR2A and hepatocellular carcinoma.