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Current therapies are associated with substantial morbidity, and prognosis remains poor in high-risk subgroups, particularly those with\n                    <jats:italic>TP53<\/jats:italic>\n                    mutations or relapsed disease. Cellular senescence is a tumor-suppressive program implicated in MB, but its role in antitumor 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-B56\u03b1 induced senescence in MB models. PP2Ac-deficient senescent cells exhibited increased MHC class I expression and enhanced immunogenicity. In syngeneic orthotopic models, PP2Ac loss prolonged survival in an immune- and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell\u2013dependent 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 (LNP) platform to deliver siRNA targeting\n                    <jats:italic>PPP2CA<\/jats:italic>\n                    . LNP\u2013small-interfering PP2Ac efficiently silenced PP2Ac in vitro and, when delivered locally in vivo, prolonged survival in a CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell\u2013dependent manner. Together, these findings identify PP2A as a regulator of immunogenic senescence in MB and support PP2Ac targeting as a therapeutic strategy.\n                  <\/jats:p>","DOI":"10.1172\/jci196753","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T18:06:50Z","timestamp":1778004410000},"source":"Crossref","is-referenced-by-count":1,"title":["Protein phosphatase 2A regulates senescence and immunogenicity in medulloblastoma models"],"prefix":"10.1172","volume":"136","author":[{"given":"Winson S.","family":"Ho","sequence":"first","affiliation":[{"name":"Department of Neurological Surgery, and"},{"name":"Helen Diller Comprehensive Cancer Center, UCSF, San Francisco, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isha","family":"Mondal","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, and"},{"name":"Helen Diller Comprehensive Cancer Center, UCSF, San Francisco, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Computational Biology, St. Jude Children\u2019s Research Hospital, Memphis, Tennessee, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, and"},{"name":"Helen Diller Comprehensive Cancer Center, UCSF, San Francisco, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawei","family":"Huo","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, Malnati Brain Tumor Institute of the Robert H. 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