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Gastric cancer peritoneal metastases (GCPM) are a leading cause of death in gastric cancer patients. In this study, we focused on the expression of cyclin-dependent protein kinases (CDK), essential regulators of transcription, metabolism, and cell differentiation, in GCPM. Utilizing the GSE62254 cohort, we established a CDK signature (CDKS) model comprising ten CDK gene family members. Analysis of both the GSE62254 and TCGA cohorts revealed that patients with low CDKS had a worse prognosis compared to those with high CDKS. Furthermore, patients with high CDKS demonstrated positive responses from immunotherapy, as observed in the KIM cohort. We investigated the association between CDKS and the tumor microenvironment, including immune escape mechanisms. Immunohistochemistry analysis revealed a positive correlation between CDK5 and PD-L1 expression in gastric cancer. Furthermore, we found that CDK5 knockdown led to the inhibition of PD-L1 expression in gastric cancer cells. Our findings highlight the potential of CDKS as a prognostic biomarker and an indicator of immunotherapy response in gastric cancer patients. Moreover, our study suggests that targeting CDK5 could provide a new pathway for exploring immunotherapeutic research., Competing Interests: None., (AJCR Copyright © 2023.)