The TLR2/4-MAPK pathway was activated during TIM-1+ Breg cell expansion, and targeting these signaling molecules impaired HMGB1-mediated TIM-1+Breg cell expansion and the suppressive function of TIM-1+Breg cells against CD8+ T cells, which suggest that HCC promotes the accumulation of TIM-1+Breg cells through the TLR2/4-MAPK pathway. This evidence concerns the gene HMGB1 and hepatocellular carcinoma.