PP2A Regulates Senescence and Immunogenicity in Medulloblastoma

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Current treatments carry significant morbidity, and prognosis remains poor in subgroups with TP53 mutations or relapse, underscoring the need for new therapeutic strategies. Senescence is a tumor-suppressive program disrupted in MB. We hypothesized that restoring senescence through p53-independent mechanisms could be therapeutic. Here, we identify Protein Phosphatase 2A (PP2A) as a key regulator of senescence in MB. Genetic ablation of the PP2A catalytic subunit (PP2Ac) or knockdown of the regulatory subunit PP2A-B56α induces robust senescence in TP53-mutant MB models. Senescent PP2Ac-deficient cells show increased MHC-I expression and enhanced immunogenicity. In a syngeneic orthotopic model, PP2Ac loss prolongs survival in an immune- and CD8-dependent manner, indicating enhanced immune-mediated tumor clearance. Analysis of MB patient datasets links senescence signatures with improved survival, and integrative single-cell analysis reveals reduced PP2A activity in immunogenic senescent clusters. Although the PP2A inhibitor LB-100 is under clinical investigation, it fails to cross the blood-brain barrier. To overcome this, we developed a lipid nanoparticle (LNP) formulation delivering siRNA against PP2Ac. LNP-siPP2Ac efficiently silences PP2Ac in vitro and, when locally delivered in vivo, extends survival and increases tumor MHC-I expression. These findings establish PP2A as a central modulator of senescence and immunogenicity in MB and support a therapeutic strategy that induces tumor cell senescence and enhances anti-tumor immunity for treatment of MB.