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

Acta Pharmacologica Sinica (2025)Cite this article

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 G422TN-GBM tumors (d 7), we found that CD73 and its associated adenosine metabolic signaling were significantly elevated in G422TN-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 G422TN-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 G422TN-GBM, thereby stimulating the activation of P2RY12+ microglia to exert their M1-like anti-cancer functions, as confirmed by human GBM scRNA-seq and G422TN-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.

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Fig. 1: CD73 is predominantly expressed on tumor cells in GBM tissues and associates to worse prognosis.
Fig. 2: AB680 exerts therapeutic effects in G422TN-GBM mice but does not affect G422TN-GBM cell proliferation in vitro.
Fig. 3: AB680 induces microglia M1-like phenotype transformation in vivo and in vitro.
Fig. 4: AB680 alters purine metabolism and elevates ADP and AMP levels in G422TN-GBM.
Fig. 5: P2RY12+ microglia is identified as an antitumor microglia subset in human gliomas.
Fig. 6: P2RY12+ microglia is a therapeutic effector in AB680-treated G422TN-GBM tumors.
Fig. 7: AB680 enhances the efficacy of RT/TMZ in G422TN-GBM tumors by reversing ADP signaling and inducing P2RY12+ microglia infiltration.
Fig. 8: Schematic illustration of the mechanisms by which AB680 effectively treats GBM in this article.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant No. 82173197 to XQC); the Hubei Provincial Natural Science Foundation of China (Grant No. 2024AFB978 to FL); the Jingzhou Joint Scientific Research Fund (Grant No. 2024LHY14 to FL); the Scientific Research Starting Foundation for Doctor, the First People’s Hospital of Jingzhou (Grant No. 2023DIF01 to FL); the National Natural Science Foundation of China (Grant No. 32270715 to MFL).

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  1. These authors contributed equally: Pan-pan Gao, Hai-feng Jiang.

Authors and 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

    Pan-pan Gao, Hai-feng Jiang, Yu-wen Du, Jia-xing Wu, Xin-xin Liang, Si-dao Wang, Ze-hua Ding, Xiao-hong Xu, Qi An, Cheng Miao & Xiao-qian Chen

  2. Department of Pharmacy, The First Affiliated Hospital of Yangtze University, Jingzhou, 434000, China

    Ya Shu & Feng Liu

  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

    Yu-wei Wan

  4. Department of Traumatic Surgery, Tongji Hospital affiliated Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, China

    En-zhi Yin

  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

    Xi-miao He

  6. Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Ming-feng Li

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Contributions

PPG performed experiments, acquisition and analysis of data, bioinformatics analysis, and wrote the manuscript. HFJ performed experiments, bioinformatics analysis, and wrote the manuscript. YWD, YS, EZY, JXW, XXL, SDW, ZHD, and XHX performed experiments. YWW, FL were involved in writing, review, and/or revision of the manuscript. QA and CM help experiments. XMH and MFL assisted with bioinformatics analysis and provided a server operating on the Linux platform for the purposes of our research. XQC designed the scheme of the study and wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Feng Liu or Xiao-qian Chen.

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Gao, Pp., Jiang, Hf., Du, Yw. et al. CD73 inhibitor AB680 suppresses glioblastoma in mice by inhibiting purine metabolism and promoting P2RY12+ microglia transformation. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01585-9

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