Extracellular PKM2 modulates cancer immunity by regulating macrophage polarity
Abstract Tumor controls its immunity by educating its microenvironment, including regulating polarity of tumor associated macrophages. It is well documented that cancer cells release PKM2 to facilitate tumor progression. We report here that the extracellular PKM2 (EcPKM2) modulates tumor immunity by...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer
2025-05-01
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| Series: | Cancer Immunology, Immunotherapy |
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| Online Access: | https://doi.org/10.1007/s00262-025-04050-y |
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| _version_ | 1850102309882691584 |
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| author | Guangda Peng Bin Li Hongwei Han Yi Yuan Falguni Mishra Yang Huang Zhi-Ren Liu |
| author_facet | Guangda Peng Bin Li Hongwei Han Yi Yuan Falguni Mishra Yang Huang Zhi-Ren Liu |
| author_sort | Guangda Peng |
| collection | DOAJ |
| description | Abstract Tumor controls its immunity by educating its microenvironment, including regulating polarity of tumor associated macrophages. It is well documented that cancer cells release PKM2 to facilitate tumor progression. We report here that the extracellular PKM2 (EcPKM2) modulates tumor immunity by facilitating M2 macrophage polarization in tumors. EcPKM2 interacts with integrin αvβ3 on macrophage to activate integrin-FAK-PI3K signal axis. Activation of FAK-PI3K by EcPKM2 suppresses PTEN expression, which subsequently upregulates arginase1 (Arg1) expression and activity in macrophage to facilitate M2 polarity. Our studies uncover a novel and important mechanism for modulation of tumor immunity. More importantly, an antibody against PKM2 that disrupts the interaction between EcPKM2 and integrin αvβ3 is effective in converting M2 macrophages to M1 macrophages in tumors, suggesting a new therapeutic strategy and target for cancer therapies. Combination of the anti-PKM2 antibody with checkpoint blockades provides enhanced treatment effects. |
| format | Article |
| id | doaj-art-df9723e5c71d45f78580dce488b42850 |
| institution | DOAJ |
| issn | 1432-0851 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Springer |
| record_format | Article |
| series | Cancer Immunology, Immunotherapy |
| spelling | doaj-art-df9723e5c71d45f78580dce488b428502025-08-20T02:39:47ZengSpringerCancer Immunology, Immunotherapy1432-08512025-05-0174711210.1007/s00262-025-04050-yExtracellular PKM2 modulates cancer immunity by regulating macrophage polarityGuangda Peng0Bin Li1Hongwei Han2Yi Yuan3Falguni Mishra4Yang Huang5Zhi-Ren Liu6Department of Biology, Georgia State UniversityDepartment of Biology, Georgia State UniversityDepartment of Biology, Georgia State UniversityDepartment of Biology, Georgia State UniversityDepartment of Biology, Georgia State UniversityDepartment of Biology, Georgia State UniversityDepartment of Biology, Georgia State UniversityAbstract Tumor controls its immunity by educating its microenvironment, including regulating polarity of tumor associated macrophages. It is well documented that cancer cells release PKM2 to facilitate tumor progression. We report here that the extracellular PKM2 (EcPKM2) modulates tumor immunity by facilitating M2 macrophage polarization in tumors. EcPKM2 interacts with integrin αvβ3 on macrophage to activate integrin-FAK-PI3K signal axis. Activation of FAK-PI3K by EcPKM2 suppresses PTEN expression, which subsequently upregulates arginase1 (Arg1) expression and activity in macrophage to facilitate M2 polarity. Our studies uncover a novel and important mechanism for modulation of tumor immunity. More importantly, an antibody against PKM2 that disrupts the interaction between EcPKM2 and integrin αvβ3 is effective in converting M2 macrophages to M1 macrophages in tumors, suggesting a new therapeutic strategy and target for cancer therapies. Combination of the anti-PKM2 antibody with checkpoint blockades provides enhanced treatment effects.https://doi.org/10.1007/s00262-025-04050-yPyruvate kinase M2MacrophageIntegrin αvβ3Cancer immunotherapyArginase1Glycolysis |
| spellingShingle | Guangda Peng Bin Li Hongwei Han Yi Yuan Falguni Mishra Yang Huang Zhi-Ren Liu Extracellular PKM2 modulates cancer immunity by regulating macrophage polarity Cancer Immunology, Immunotherapy Pyruvate kinase M2 Macrophage Integrin αvβ3 Cancer immunotherapy Arginase1 Glycolysis |
| title | Extracellular PKM2 modulates cancer immunity by regulating macrophage polarity |
| title_full | Extracellular PKM2 modulates cancer immunity by regulating macrophage polarity |
| title_fullStr | Extracellular PKM2 modulates cancer immunity by regulating macrophage polarity |
| title_full_unstemmed | Extracellular PKM2 modulates cancer immunity by regulating macrophage polarity |
| title_short | Extracellular PKM2 modulates cancer immunity by regulating macrophage polarity |
| title_sort | extracellular pkm2 modulates cancer immunity by regulating macrophage polarity |
| topic | Pyruvate kinase M2 Macrophage Integrin αvβ3 Cancer immunotherapy Arginase1 Glycolysis |
| url | https://doi.org/10.1007/s00262-025-04050-y |
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