Comprehensive Analysis of SHC1 Expression and Its Role in Glioblastoma Progression and Immune Modulation

Abstract SHC adaptor protein 1 (SHC1) encodes three protein isoforms, including p66Shc, a well-characterized mediator of oxidative stress responses. Despite evidence implicating SHC1 in tumorigenesis and progression, its pan-cancer expression landscape and functional significance in glioblastoma (GBM) remain incompletely characterized. Herein, we integrated multi-omics datasets from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) project, and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) to comprehensively characterize SHC1 expression patterns, prognostic relevance, and associations with the immune landscape across 33 cancer types. Our analysis showed significant SHC1 upregulation in several malignancies, including GBM, which correlated with unfavorable prognosis and immunosuppressive cell infiltration. Functional assays further showed that silencing SHC1 in GBM cells significantly impaired proliferative, migratory, and invasive capacities, accompanied by G₂/M cell-cycle arrest, increased apoptosis, and enhanced responsiveness to temozolomide (TMZ). Integrative transcriptomic and proteomic analyses identified CCNB1 as a key downstream effector mediating SHC1-driven cell cycle progression; restoration of CCNB1 partially reversed the phenotypic effects of SHC1 loss. In vivo experiments further demonstrated that SHC1 silencing restrained intracranial tumor progression and extended survival in both immunodeficient and immunocompetent mouse models. Single-cell RNA sequencing also indicated a reshaped tumor immune microenvironment, characterized by reduced immunosuppressive macrophages and increased CD8⁺ T cell infiltration. Collectively, these results identify SHC1 as a multifaceted contributor to GBM malignancy by supporting proliferation, DNA repair, and immune escape, underscoring its potential as both a therapeutic target and a prognostic biomarker in GBM.