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ResearchIn-Press PreviewImmunologyOncology Open Access | 10.1172/JCI196753

Protein phosphatase 2A regulates senescence and immunogenicity in medulloblastoma models

Winson S. Ho,1 Isha Mondal,1 Jingjing Liu,2 Raymond Sun,1 Jiawei Huo,3 Chao Gao,1 Oishika Das,1 Daren Tieu,1 Jingqi Sun,3 Hanchen Lin,3 Peng Zhang,3 Jiyang Yu,2 and Rongze Olivia Lu1

1Department of Neurological Surgery, University of California San Francisco, San Francisco, United States of America

2Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, United States of America

3Department of Neurological Surgery, Northwestern University, Chicago, United States of America

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1Department of Neurological Surgery, University of California San Francisco, San Francisco, United States of America

2Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, United States of America

3Department of Neurological Surgery, Northwestern University, Chicago, United States of America

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1Department of Neurological Surgery, University of California San Francisco, San Francisco, United States of America

2Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, United States of America

3Department of Neurological Surgery, Northwestern University, Chicago, United States of America

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1Department of Neurological Surgery, University of California San Francisco, San Francisco, United States of America

2Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, United States of America

3Department of Neurological Surgery, Northwestern University, Chicago, United States of America

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1Department of Neurological Surgery, University of California San Francisco, San Francisco, United States of America

2Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, United States of America

3Department of Neurological Surgery, Northwestern University, Chicago, United States of America

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1Department of Neurological Surgery, University of California San Francisco, San Francisco, United States of America

2Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, United States of America

3Department of Neurological Surgery, Northwestern University, Chicago, United States of America

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1Department of Neurological Surgery, University of California San Francisco, San Francisco, United States of America

2Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, United States of America

3Department of Neurological Surgery, Northwestern University, Chicago, United States of America

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1Department of Neurological Surgery, University of California San Francisco, San Francisco, United States of America

2Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, United States of America

3Department of Neurological Surgery, Northwestern University, Chicago, United States of America

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1Department of Neurological Surgery, University of California San Francisco, San Francisco, United States of America

2Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, United States of America

3Department of Neurological Surgery, Northwestern University, Chicago, United States of America

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1Department of Neurological Surgery, University of California San Francisco, San Francisco, United States of America

2Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, United States of America

3Department of Neurological Surgery, Northwestern University, Chicago, United States of America

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1Department of Neurological Surgery, University of California San Francisco, San Francisco, United States of America

2Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, United States of America

3Department of Neurological Surgery, Northwestern University, Chicago, United States of America

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1Department of Neurological Surgery, University of California San Francisco, San Francisco, United States of America

2Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, United States of America

3Department of Neurological Surgery, Northwestern University, Chicago, United States of America

Find articles by Yu, J. in: PubMed | Google Scholar |

1Department of Neurological Surgery, University of California San Francisco, San Francisco, United States of America

2Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, United States of America

3Department of Neurological Surgery, Northwestern University, Chicago, United States of America

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Published May 5, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI196753.
Copyright © 2026, Ho et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published May 5, 2026 - Version history
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Abstract

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Current therapies are associated with substantial morbidity, and prognosis remains poor in high-risk subgroups, particularly those with TP53 mutations or relapsed disease. Cellular senescence is a tumor-suppressive program implicated in MB, but its role in anti-tumor immunity remains incompletely understood. We found that protein phosphatase 2A (PP2A) regulated immunogenic senescence in MB. Genetic ablation of the PP2A catalytic subunit, PP2Ac, or depletion of the regulatory subunit PP2A-B56α induced senescence in MB models. PP2Ac-deficient senescent cells exhibited increased MHC-I expression and enhanced immunogenicity. In syngeneic orthotopic models, PP2Ac loss prolonged survival in an immune- and CD8+ T cell-dependent manner. Analysis of patient datasets showed that senescence-associated gene signatures correlated with improved survival. Single-cell transcriptomic analysis further revealed that senescent MB cells were heterogeneous and that reduced PP2A activity was associated with an immunogenic senescence state. Because the PP2A inhibitor LB-100 has limited potency and off-target effects, we developed a lipid nanoparticle platform to deliver siRNA targeting PPP2CA. LNP-siPP2Ac efficiently silenced PP2Ac in vitro and, when delivered locally in vivo, prolonged survival in a CD8+ T cell-dependent manner. Together, these findings identify PP2A as a regulator of immunogenic senescence in MB and support PP2Ac targeting as a therapeutic strategy.

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