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Glycogen synthase kinase-3β (GSK-3β), a serine/threonine kinase, has been implicated in the pathogenesis of many cancers, with involvement in cell-cycle regulation, apoptosis, and immune response. Small-molecule GSK-3β inhibitors are currently undergoing clinical investigation. Tumor sequencing has revealed genomic alterations in , yet an assessment of the genomic landscape in malignancies is lacking. This study assessed >100,000 tumors from two databases to analyze alterations. GSK-3β expression and immune cell infiltrate data were analyzed across cancer types, and programmed death-ligand 1 (PD-L1) expression was compared between -mutated and wild-type tumors. was mutated at a rate of 1%. The majority of mutated residues were in the kinase domain, with frequent mutations occurring in a GSK-3β substrate binding pocket. Uterine endometrioid carcinoma was the most commonly mutated (4%) tumor, and copy-number variations were most commonly observed in squamous histologies. Significant differences across cancer types for -mutated tumors were observed for B cells ( = 0.018), monocytes ( = 0.002), dendritic cells ( = 0.005), neutrophils ( = 0.0003), and endothelial cells ( = 0.014). mRNA expression was highest in melanoma. The frequency of PD-L1 expression was higher among -mutated tumors compared with wild type in colorectal cancer ( = 0.03), endometrial cancer ( = 0.05), melanoma ( = 0.02), ovarian carcinoma ( = 0.0001), and uterine sarcoma ( = 0.002). Overall, molecular alterations were detected in approximately 1% of solid tumors, tumors with mutations displayed a microenvironment with increased infiltration of B cells, and mutations were associated with increased PD-L1 expression in selected histologies. These results advance the understanding of GSK-3β complex signaling network interfacing with key pathways involved in carcinogenesis and immune response.