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

• DOI: 10.1126/sciadv.ads8597
• Publication Date: 2025-05-02T17:58:36Z
• Authors: Wei-Feng Qu; Gui-Qi Zhu; Rui Yang; Tian-Hao Chu; Zhi-Qi Guan; Run Huang; Meng-Xin Tian; Xi-Fei Jiang; Chen-Yang Tao; Yuan Fang; Jun Gao; Xiao-Ling Wu; Jia-Feng Chen; Qian-Fu Zhao; Yi Wang; Yi-Chao Bu; Jian Zhou; Jia Fan; Wei-Ren Liu; Zheng Tang; Ying-Hong Shi

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 of great significance. Although high-mobility group box 2 (HMGB2) has been reported to be crucial HCC prognosis, its role the microenvironment remains unclear. Here, we found HMGB2 + CD8 cells as being associated with resistance anti–PD-1 through single-cell RNA sequencing. Mechanistically, impaired oxidative phosphorylation inactivated interferon-γ cells, reducing antitumor effector function. Tannic acid, specific inhibitor HMGB2, synergized PD-1 antibody attenuate reverse exhaustion. Our findings highlight unique an molecule. Targeting on both contributed promising strategies HCC.