Targeting HMGB2 acts as dual immunomodulator by bolstering CD8+ T cell function and inhibiting tumor growth in hepatocellular carcinoma [ATAC-seq]

T cell exhaustion is a critical obstacle for durable treatment response in hepatocellular carcinoma (HCC). Developing drugs that control tumor growth and simultaneously bolster immune function is of great significance. The transcriptional regulator high mobility group box 2 (HMGB2) has emerged as a risk factor in prognosis of HCC. However, the role of HMGB2 in HCC tumor microenvironment (TME) is poorly understood. Here, we discovered HMGB2+ CD8+ T cells as being associated with T cell exhaustion and resistance to anti-PD-1 treatment through single-cell RNA sequencing of human and murine HCC tissues. Mechanistically, HMGB2 impaired the mitochondrial oxidative phosphorylation in CD8+ T cells by increasing the ubiquitination of NRF2, thus reduced the antitumor effector function. In tumor cells, HMGB2 inactivated the interferon-γ (IFN-γ) response through TRIM24/STAT1 pathway, inhibiting susceptibility and recruitment to effector T cells. Tannic acid, a specific inhibitor of HMGB2, synergized with PD-1 antibody to attenuate tumor growth and reverse T cell exhaustion. Collectively, this study revealed that HMGB2, a T cell exhaustion associated molecule, contributed to tumor immune escape by dual action on CD8+ T cells and tumor cells. These data also provided translational insight into synergistic treatment strategies.