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Gastric cancer (GC) is the most common form of gastrointestinal cancer, with a high mortality rate and limited treatment options. High levels of NEK2 are associated with malignant progression and a poor prognosis in several tumors; however, the role of NEK2 in GC remains unclear. We aimed to explore the potential role of NEK2 in the oncogenesis of GC and in the shaping of the tumor microenvironment (TME). The expression levels of NEK2 were analyzed using immunohistochemistry and real-time quantitative polymerase chain reaction. We found that NEK2 expression was upregulated in GC and was a predictor of a poor prognosis. Based on Kyoto Encyclopedia of Genes and Genomes pathway enrichment and gene set enrichment analyses, multiple tumor pathways were hyperactivated in patients with high NEK2 mRNA expression. Immunological characteristics indicated that NEK2 upregulation might lead to decreased immune cell infiltration and weakened immune activity in the cancer immunity cycle. Additionally, higher frequencies of amplifications and deletions were observed in the high NEK2 expression subpopulation. Based on the TME classification, patients with high expression of NEK2 were more susceptible to targeted therapy with drugs targeting the cell cycle and DNA replication. Following verification, a NEK2-derived genomic model reliably predicted the patient prognosis; A nomogram (radiation therapy, tumor/node/metastasis staging, and the NEK2-derived risk score) was used to better estimate an individual's survival probability. In summary, our findings indicate that NEK2 plays a vital role in the tumorigenesis of GC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)