Targeting HMGB2 acts as dual immunomodulator by bolstering CD8 <sup>+</sup> T cell function and inhibiting tumor growth in hepatocellular carcinoma
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. Although high-mobility group box 2 (HMGB2) has been reported to be crucial to HCC prognosis, its role in the tumor microenvironment remains unclear. Here, we found HMGB2<sup>+</sup> CD8<sup>+</sup> T cells as being associated with immune exhaustion and resistance to anti-PD-1 treatment through single-cell RNA sequencing. Mechanistically, HMGB2 impaired the oxidative phosphorylation in CD8<sup>+</sup> T cells and inactivated the interferon-γ response in tumor cells, reducing the antitumor effector function. Tannic acid, a specific inhibitor of HMGB2, synergized with PD-1 antibody to attenuate tumor growth and reverse T cell exhaustion. Our findings highlight the unique role of HMGB2 as an immune exhaustion associated molecule. Targeting HMGB2 on both CD8<sup>+</sup> T cells and tumor cells contributed to promising treatment strategies for HCC.
Authors
- Jiafeng Chen (ORCID: https://orcid.org/0000-0002-1088-5338)
- Tian-Hao Chu
- Rui Yang
- Wei‐Feng Qu
- Qianfu Zhao (ORCID: https://orcid.org/0009-0007-1032-7612)
- Xiaoling Wu (ORCID: https://orcid.org/0000-0001-8038-1138)
- Gui‐Qi Zhu (ORCID: https://orcid.org/0000-0001-5089-6923)
- Ying‐Hong Shi (ORCID: https://orcid.org/0000-0002-1833-8988)
- Yi Wang (ORCID: https://orcid.org/0000-0002-9974-7440)
- Jia Fan (ORCID: https://orcid.org/0000-0001-5158-629X)
- Jian Zhou (ORCID: https://orcid.org/0000-0002-2118-1117)
- Meng-Xin Tian
- Zhi‐Zhong Guan (ORCID: https://orcid.org/0009-0001-4765-0137)
- Zheng Tang (ORCID: https://orcid.org/0000-0003-0256-4494)
- Weiren Liu (ORCID: https://orcid.org/0000-0003-3393-1322)
- Run Huang (ORCID: https://orcid.org/0009-0009-7467-4896)
- Yuan Fang (ORCID: https://orcid.org/0000-0002-1931-2632)
- Jun Gao (ORCID: https://orcid.org/0000-0001-9072-4245)
- Chen-Yang Tao (ORCID: https://orcid.org/0000-0003-0496-6673)
- Xi‐Fei Jiang
- Yichao Bu (ORCID: https://orcid.org/0009-0002-1283-3547)
Institutions
- Sun Yat-sen University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Fudan University (CN)
- Zhongshan Hospital (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
Publication Details
- Journal
- Science Advances
- Published
- 2025-05-02
- DOI
- https://doi.org/10.1126/sciadv.ads8597
- Citations
- 6
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 5.23