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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| Format: | Article |
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Wiley
2025-07-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202416501 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jing‐Yan Cheng |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-fbb1fb1b4e4d41d4acf24eafdca33fc1 |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-fbb1fb1b4e4d41d4acf24eafdca33fc12025-08-20T02:40:00ZengWileyAdvanced Science2198-38442025-07-011227n/an/a10.1002/advs.202416501Tumor‐Associated Glycan Exploits Adenosine Receptor 2A Signaling to Facilitate Immune EvasionJing‐Yan Cheng0Hsiu‐Hui Tsai1Jung‐Tung Hung2Tsai‐Hsien Hung3Chun‐Cheng Lin4Chien‐Wei Lee5Zi‐Chi Lo6Jing‐Rong Huang7Shih‐Pin Chiou8Yenlin Huang9Shih‐Hsiang Chen10Chun‐Nan Yeh11John Yu12Alice L. Yu13Institute of Stem Cell and Translational Cancer ResearchChang Gung Memorial Hospital Linkou Medical Center15, Wenhua 1st Rd. Taoyuan 333 TaiwanInstitute of Stem Cell and Translational Cancer ResearchChang Gung Memorial Hospital Linkou Medical Center15, Wenhua 1st Rd. Taoyuan 333 TaiwanInstitute of Stem Cell and Translational Cancer ResearchChang Gung Memorial Hospital Linkou Medical Center15, Wenhua 1st Rd. Taoyuan 333 TaiwanInstitute of Stem Cell and Translational Cancer ResearchChang Gung Memorial Hospital Linkou Medical Center15, Wenhua 1st Rd. Taoyuan 333 TaiwanDepartment of ChemistryNational Tsing Hua University101, Sec. 2, Kuang‐Fu Rd. Hsinchu 300 TaiwanInstitute of Stem Cell and Translational Cancer ResearchChang Gung Memorial Hospital Linkou Medical Center15, Wenhua 1st Rd. Taoyuan 333 TaiwanInstitute of Stem Cell and Translational Cancer ResearchChang Gung Memorial Hospital Linkou Medical Center15, Wenhua 1st Rd. Taoyuan 333 TaiwanInstitute of Stem Cell and Translational Cancer ResearchChang Gung Memorial Hospital Linkou Medical Center15, Wenhua 1st Rd. Taoyuan 333 TaiwanInstitute of Stem Cell and Translational Cancer ResearchChang Gung Memorial Hospital Linkou Medical Center15, Wenhua 1st Rd. Taoyuan 333 TaiwanInstitute of Stem Cell and Translational Cancer ResearchChang Gung Memorial Hospital Linkou Medical Center15, Wenhua 1st Rd. Taoyuan 333 TaiwanDepartment of PediatricsDivision of Hematology‐OncologyChang Gung Memorial Hospital5, Fuxing St. Taoyuan 333 TaiwanSchool of MedicineNational Tsing Hua University101, Sec. 2, Kuang‐Fu Rd. Hsinchu 300 TaiwanInstitute of Stem Cell and Translational Cancer ResearchChang Gung Memorial Hospital Linkou Medical Center15, Wenhua 1st Rd. Taoyuan 333 TaiwanInstitute of Stem Cell and Translational Cancer ResearchChang Gung Memorial Hospital Linkou Medical Center15, Wenhua 1st Rd. Taoyuan 333 TaiwanAbstract 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.https://doi.org/10.1002/advs.202416501Adenosine receptor 2AGlobo H ceramideTRAXTreg |
| spellingShingle | 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 Tumor‐Associated Glycan Exploits Adenosine Receptor 2A Signaling to Facilitate Immune Evasion Advanced Science Adenosine receptor 2A Globo H ceramide TRAX Treg |
| title | Tumor‐Associated Glycan Exploits Adenosine Receptor 2A Signaling to Facilitate Immune Evasion |
| title_full | Tumor‐Associated Glycan Exploits Adenosine Receptor 2A Signaling to Facilitate Immune Evasion |
| title_fullStr | Tumor‐Associated Glycan Exploits Adenosine Receptor 2A Signaling to Facilitate Immune Evasion |
| title_full_unstemmed | Tumor‐Associated Glycan Exploits Adenosine Receptor 2A Signaling to Facilitate Immune Evasion |
| title_short | Tumor‐Associated Glycan Exploits Adenosine Receptor 2A Signaling to Facilitate Immune Evasion |
| title_sort | tumor associated glycan exploits adenosine receptor 2a signaling to facilitate immune evasion |
| topic | Adenosine receptor 2A Globo H ceramide TRAX Treg |
| url | https://doi.org/10.1002/advs.202416501 |
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