Chemoresistance and Immune Suppression in Gastric Cancer Are Driven by PPDPF Overexpression.

Abstract

Gastric cancer (GC) remains a lethal malignancy, and there is a pressing need for novel therapeutic targets. This study aimed to identify key oncogenic drivers in GC. Through integrative bioinformatic analysis of TCGA and GEO transcriptomic datasets, coupled with single-cell sequencing data, we identified PPDPF as a candidate gene that is specifically enriched in malignant gastric epithelial cells and associated with poor prognosis. Functional in vitro assays confirmed that PPDPF overexpression significantly enhanced the viability, migration, and invasion of GC cell lines. Mechanistically, RNA sequencing revealed that PPDPF broadly suppresses antitumor immunity, notably by downregulating key ligands of the CXCR3 axis and correlating with specific immune checkpoint profiles. Furthermore, bioinformatic predictions combined with experimental validation (RT-PCR, ELISA, and drug sensitivity assays) demonstrated that high PPDPF expression fosters an immunosuppressive tumor microenvironment and confers resistance to 5-Fluorouracil and Oxaliplatin. In conclusion, this study is the first to establish PPDPF as a critical molecular driver that promotes malignant progression, orchestrates an immunosuppressive microenvironment, and mediates chemotherapy resistance in gastric cancer. Our findings position PPDPF as a potential novel prognostic biomarker and therapeutic target, providing a theoretical foundation for developing personalized treatment strategies for patients with gastric cancer.