Increased TIM − 1+ Breg cell frequency was closely associated with HCC malignant progression and poor prognosis, which evidently proved to be mediated by tumor sourced high mobility group box 1 (HMGB1) via toll like receptor 2/4 (TLR2/4)-mitogen activated protein kinase (MAPK) pathway. The gene discussed is HMGB1; the disease is hepatocellular carcinoma.