m6A reader YTHDF2 orchestrates CD8+ T cell infiltration to promote pancreatic cancer progression and predicts clinical outcome

Pancreatic cancer has emerged as one of the most lethal malignancies, characterized by rising morbidity and mortality rates. Research has demonstrated that N6-methyladenosine (m 6 A) modification of RNA significantly influences RNA metabolism, and dysregulation of m 6 A is implicated in various human diseases. A clearer picture of how the divergent m 6 A methylation patterns affect immunological microenvironment in pancreatic cancer is still unknown. Based on an analysis of RNA-sequencing (RNA-seq) data from the TCGA, GEO, and GTEx databases, we predicted and validated the expression of YTHDF2. Apoptosis and cell cycle analyses of YTHDF2 were conducted using flow cytometry, and a subcutaneous transplantation tumor model was established in BALB/c nude mice. The immune infiltration status and Weighted Gene Co-expression Network Analysis (WGCNA) were employed to evaluate cellular immunity and identify downstream target genes associated with the CD8 + T cell module. Additionally, machine learning-based integrative approaches were utilized to generate a predictive signature. The Western blot technique was employed to quantify YTHDF2 expression levels in PDAC cell lines and tissues. WGCNA and PPI unveiled TFG as the core gene regulation network conducting the function of the CD8 + T cell. Quantitative reverse transcription PCR (qRT-PCR) assays were conducted to confirm the reduction in TFG expression subsequent to YTHDF2 knockdown. Integrative analyses using large-scale genomic data sets were conducted to reveal that YTHDF2 could affect pancreatic cancer cell apoptosis and the cell cycle, promote malignant biologic processes, and gene regulation in immune cells. YTHDF2 potentially modulates crucial molecular subgroups of immune checkpoint molecules in CD8 + T cells, thereby enhancing tumor immunogenicity and promoting anti-tumor immune responses.

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