Tumor derived exosome-activated B cells strongly express Tim-1 protein and have inhibitory activity against CD8 T cells. Exogenous HMGB1 activates B cells and promotes the expansion of Tim-1 Breg cells through Toll-like receptor (TLR) 2/4 and mitogen-activated protein kinase (MAPK) signaling pathways. Accumulation of TIM-1BREG cells in tumors is associated with advanced disease, early recurrence, and reduced survival in HCC patients. Here, HMGB1 is linked to hepatocellular carcinoma.