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CD73 inhibitor AB680 suppresses glioblastoma in mice by inhibiting purine metabolism and promoting P2RY12<sup>+</sup> microglia transformation.

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.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS11084 | MetaboLights | 2025-08-04

REPOSITORIES: MetaboLights

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			Action	DRS
	HFX10_2225399_CN_QC1.raw	Raw
	HFX10_2225399_CN_QC2.raw	Raw
	HFX10_2225399_CN_QC3.raw	Raw
	HFX10_2225399_CN_blank.raw	Raw
	HFX10_2225399_CP_QC1.raw	Raw

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CD73 inhibitor AB680 suppresses glioblastoma in mice by inhibiting purine metabolism and promoting P2RY12<sup>+</sup> microglia transformation.

Gao Pan-Pan PP Jiang Hai-Feng HF Du Yu-Wen YW Shu Ya Y Wan Yu-Wei YW Yin En-Zhi EZ Wu Jia-Xing JX Liang Xin-Xin XX Wang Si-Dao SD Ding Ze-Hua ZH Xu Xiao-Hong XH An Qi Q Miao Cheng C He Xi-Miao XM Li Ming-Feng MF Liu Feng F Chen Xiao-Qian XQ

Acta pharmacologica Sinica 20250611 11

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 CD7 ...[more]

PMID: 40500344

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Project description:A significant challenge for chimeric antigen receptor (CAR) T cell therapy against glioblastoma (GBM) is its immunosuppressive tumor microenvironment (TME), which is densely populated and supported by protumoral glioma-associated microglia and macrophages (GAMs). Targeting CD47, a don't-eat-me signal overexpressed by tumor cells, disrupts the CD47-SIRPalpha axis and induces GAM phagocytic function. However, antibody-mediated CD47 blockade monotherapy is associated with toxicity and low bioavailability in solid tumors. To overcome these limitations, we combined local CAR T cell therapy with paracrine GAM modulation to effectively eliminate GBM. To this end, we engineered a new CAR T cell against epidermal growth factor receptor variant III (EGFRvIII) that constitutively secretes a signal regulatory protein gamma (SIRPgamma)-related protein (SGRP) with high affinity to CD47. Anti-EGFRvIII-SGRP CAR T cells eliminated EGFRvIII+ GBM in a dose-dependent manner in vitro and eradicated orthotopically xenografted EGFRvIII-mosaic GBM by locoregional application in vivo. This resulted in significant tumor-free long-term survival, followed by partial tumor control upon tumor re-challenge. Combining anti-CD47 antibodies with anti-EGFRvIII CAR T cells failed to achieve a similar therapeutic effect, underscoring the importance of sustained paracrine GAM modulation. Multidimensional brain immunofluorescence microscopy and in-depth spectral flow cytometry on GBM-xenografted brains showed that anti-EGFRvIII-SGRP CAR T cells accelerated GBM clearance, increased CD68+ cell trafficking to tumor scar sites and promoted GAM-mediated tumor cell uptake. In a peripheral lymphoma mouse xenograft model, anti-CD19-SGRP CAR T cells had superior efficacy to conventional anti-CD19 CAR T cells. Validation on human GBM explants revealed that anti-EGFRvIII-SGRP CAR T cells had a similar tumor-killing capacity to anti-EGFRvIII CAR monotherapy but showed a slight improvement in the maintenance of tumor-infiltrated CD14+ cells. Thus, local anti-EGFRvIII-SGRP CAR T cell therapy combines the potent antitumor effect of engineered T cells with the modulation of the surrounding innate immune TME. This results in the additive elimination of bystander EGFRvIII- tumor cells in a manner that overcomes the main mechanisms of CAR T cell therapy resistance, including tumor innate immune suppression and antigen escape.

Dataset Information

CD73 inhibitor AB680 suppresses glioblastoma in mice by inhibiting purine metabolism and promoting P2RY12<sup>+</sup> microglia transformation.

Dataset's files

Publications

CD73 inhibitor AB680 suppresses glioblastoma in mice by inhibiting purine metabolism and promoting P2RY12<sup>+</sup> microglia transformation.

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Dataset Information

CD73 inhibitor AB680 suppresses glioblastoma in mice by inhibiting purine metabolism and promoting P2RY12<sup>+</sup> microglia transformation.

Dataset's files

Publications

CD73 inhibitor AB680 suppresses glioblastoma in mice by inhibiting purine metabolism and promoting P2RY12&lt;sup&gt;+&lt;/sup&gt; microglia transformation.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

CD73 inhibitor AB680 suppresses glioblastoma in mice by inhibiting purine metabolism and promoting P2RY12<sup>+</sup> microglia transformation.