CD73 inhibitor AB680 suppresses glioblastoma in mice by inhibiting purine metabolism and promoting P2RY12+ microglia transformation

Pan-Pan Gao; Hai-Feng Jiang; Yu-Wen Du; Ya Shu; Yu-Wei Wan; En-Zhi Yin; Jia-Xing Wu; Xin-Xin Liang; Si-Dao Wang; Ze-Hua Ding; Xiao-Hong Xu; Qi An; Cheng Miao; Xi-Miao He; Ming-Feng Li; Feng Liu; Xiao-Qian Chen

doi:10.1038/s41401-025-01585-9

CD73 inhibitor AB680 suppresses glioblastoma in mice by inhibiting purine metabolism and promoting P2RY12⁺ microglia transformation

Acta Pharmacol Sin. 2025 Jun 11. doi: 10.1038/s41401-025-01585-9. Online ahead of print.

Authors

Pan-Pan Gao^#¹, Hai-Feng Jiang^#¹, Yu-Wen Du¹, Ya Shu², Yu-Wei Wan³, En-Zhi Yin⁴, Jia-Xing Wu¹, Xin-Xin Liang¹, Si-Dao Wang¹, Ze-Hua Ding¹, Xiao-Hong Xu¹, Qi An¹, Cheng Miao¹, Xi-Miao He⁵, Ming-Feng Li⁶, Feng Liu⁷, Xiao-Qian Chen⁸

Affiliations

¹ Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Key Laboratory of Neurological Diseases, Ministry of Education; Hubei Provincial Key Laboratory of Neurological Diseases, Huazhong University of Science and Technology, Wuhan, 430030, China.
² Department of Pharmacy, The First Affiliated Hospital of Yangtze University, Jingzhou, 434000, China.
³ School of Public Health, Jiangxi Medical College, Nanchang University, Jiangxi Provincial Key Laboratory of Disease Prevention and Public Health, Nanchang University, Nanchang, 330031, China.
⁴ Department of Traumatic Surgery, Tongji Hospital affiliated Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, China.
⁵ Department of Physiology, School of Basic Medicine, Tongji Medical College, Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and Technology, Wuhan, 430030, China.
⁶ Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
⁷ Department of Pharmacy, The First Affiliated Hospital of Yangtze University, Jingzhou, 434000, China. lftjmu@163.com.
⁸ Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Key Laboratory of Neurological Diseases, Ministry of Education; Hubei Provincial Key Laboratory of Neurological Diseases, Huazhong University of Science and Technology, Wuhan, 430030, China. chenxq@mails.tjmu.edu.cn.

^# Contributed equally.

PMID: 40500344
DOI: 10.1038/s41401-025-01585-9

Abstract

CD73 (ecto-5'-nucleotidase) is a metabolic immune checkpoint that dephosphorylates AMP to produce adenosine. Adenosine plays a pivotal role in immunosuppressive tumor microenvironment (TME) through adenosine receptors expressed on various immune cells. AB680, a specific CD73 inhibitor, is currently undergoing clinical trials for highly refractory cancers. In this study, we investigated the antitumor effects and mechanisms of AB680 in glioblastoma (GBM). By analyzing the expression pattern of CD73 across all cell types in orthotopic naïve G422^TN-GBM tumors (d 7), we found that CD73 and its associated adenosine metabolic signaling were significantly elevated in G422^TN-GBM cells compared to all other cell types. High CD73 expression was also observed in human GBM samples and was correlated with shorter patient survival. Administration of AB680 significantly prolonged survival in G422^TN-GBM-bearing mice, reduced tumor size, cell proliferation, angiogenesis, and enhanced microglia activation and anti-tumor immune responses. Metabolomic analysis revealed that AB680 markedly increased ADP and AMP levels in the TME of orthotopic G422^TN-GBM, thereby stimulating the activation of P2RY12⁺ microglia to exert their M1-like anti-cancer functions, as confirmed by human GBM scRNA-seq and G422^TN-GBM snRNA-seq data. Furthermore, AB680 combined with RT/TMZ exhibited synergistic therapeutic effects by reversing RT/TMZ-induced increases in adenosine levels and promoting the transformation of P2RY12⁺ microglia. Overall, this study demonstrates that targeting CD73 with AB680 alters purine metabolism in the GBM microenvironment, promotes the transformation of P2RY12⁺ microglia, and triggers robust anti-tumor immune responses. These results support the rationale for AB680-based therapeutic clinical trials for GBM.

Keywords: AB680; CD73; P2Y12 receptor; glioblastoma; microglia; purine metabolism.