Targeting site-specific N-glycosylated B7H3 induces potent antitumor immunity

Yun Huang, Wen-Qing Zhong, Xiao-Yu Yang, Jia-Lu Shan, Ling Zhou, Zhi-Ling Li, Yi-Qing Guo, Kai-Ming Zhang, Tian Du, Hai-Liang Zhang, Bing-Xin Hu, Yu-Hong Chen, Dong Yang, Gong-Kan Feng, Jun Tang (), Xiao-Feng Zhu () and Rong Deng ()
Additional contact information
Yun Huang: Sun Yat-sen University Cancer Center
Wen-Qing Zhong: Sun Yat-sen University Cancer Center
Xiao-Yu Yang: Sun Yat-sen University Cancer Center
Jia-Lu Shan: Sun Yat-sen University Cancer Center
Ling Zhou: Sun Yat-sen University Cancer Center
Zhi-Ling Li: Sun Yat-sen University Cancer Center
Yi-Qing Guo: Sun Yat-sen University Cancer Center
Kai-Ming Zhang: Sun Yat-sen University Cancer Center
Tian Du: Sun Yat-sen University Cancer Center
Hai-Liang Zhang: Sun Yat-sen University Cancer Center
Bing-Xin Hu: Sun Yat-sen University Cancer Center
Yu-Hong Chen: Sun Yat-sen University Cancer Center
Dong Yang: Sun Yat-sen University Cancer Center
Gong-Kan Feng: Sun Yat-sen University Cancer Center
Jun Tang: Sun Yat-sen University Cancer Center
Xiao-Feng Zhu: Sun Yat-sen University Cancer Center
Rong Deng: Sun Yat-sen University Cancer Center

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract B7H3, an immune checkpoint molecule, is a highly N-glycosylated membrane protein. However, the key glycosylated asparagine residues that mediate the function of the B7H3 protein are still unclear. Here we identify that N-glycans attached to asparagine residues N91/309 and N104/322 are required for proper B7H3 localization on the cell surface membrane. We demonstrate that mutations in these two pairs of N-glycosylation sites induce ER accumulation of B7H3 by blocking its ER-to-Golgi translocation and subsequently promote its degradation via the endoplasmic reticulum-associated protein degradation pathway. Additional evidence suggests that N-glycosylation at N91/309 and N104/322 of B7H3 is essential for its inhibition of T-cell proliferation and activation. More importantly, a monoclonal antibody, Ab-82, preferentially targeting B7H3 glycosylated at N91/309 and N104/322 is developed, which exhibits the ability to elicit cytotoxic T lymphocyte-mediated antitumor immunity via B7H3 internalization. Together, these findings offer a rationale for targeting glycosylated B7H3 as a potential strategy for immunotherapy.

Date: 2025
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DOI: 10.1038/s41467-025-58740-3

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