Tumor‐Associated Glycan Exploits Adenosine Receptor 2A Signaling to Facilitate Immune Evasion

Tumor‐Associated Glycan Exploits Adenosine Receptor 2A Signaling to Facilitate Immune Evasion

Abstract Adenosine signaling is a crucial immunosuppressive pathway within the tumor microenvironment, making it a promising target for cancer therapy. In this study, it is demonstrated that Globo H ceramide (GHCer), the most prevalent tumor‐associated glycosphingolipid, influences the tumor microen...

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Main Authors: Jing‐Yan Cheng, Hsiu‐Hui Tsai, Jung‐Tung Hung, Tsai‐Hsien Hung, Chun‐Cheng Lin, Chien‐Wei Lee, Zi‐Chi Lo, Jing‐Rong Huang, Shih‐Pin Chiou, Yenlin Huang, Shih‐Hsiang Chen, Chun‐Nan Yeh, John Yu, Alice L. Yu
Format: Article
Language:English
Published: Wiley 2025-07-01
Series:Advanced Science
Subjects:
Adenosine receptor 2A
Globo H ceramide
TRAX
Treg
Online Access:https://doi.org/10.1002/advs.202416501
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Summary:Abstract Adenosine signaling is a crucial immunosuppressive pathway within the tumor microenvironment, making it a promising target for cancer therapy. In this study, it is demonstrated that Globo H ceramide (GHCer), the most prevalent tumor‐associated glycosphingolipid, influences the tumor microenvironment by activating adenosine signaling, which results in dual immunosuppressive effects on T cells. It is demonstrated that GHCer interacts with the adenosine receptor 2A (A2AR), triggering cyclic AMP (cAMP) and protein kinase A (PKA) signaling. This interaction leads to a reduction in the proliferation of CD4+ T cells while simultaneously promoting the differentiation of regulatory T cells (Tregs). Furthermore, GHCer enhances the suppressive capacity of Treg cells by upregulating inhibitory molecules such as Lymphocyte‐activation gene 3 (LAG3), cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4), Programmed cell death 1 ligand 1 (PD‐L1), and it stimulates the secretion of the immunosuppressive cytokine Interleukin 35 (IL‐35). Additionally, GHCer‐induced Tregs express CD39 and CD73, which further enhances adenosine production and creates a positive feedback loop in the adenosinergic pathway and A2AR signaling. Mechanistically, it is found that GHCer forms a complex with TRAX (translin‐associated factor‐X) and the C‐terminus of A2AR, which facilitates the activation of A2AR and promotes an immunosuppressive tumor microenvironment.
ISSN:2198-3844

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