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Background  Pancreatic adenocarcinoma (PAAD) is one of the most malignant cancers and has a poor prognosis. As a critical RNA modification, 5-methylcytosine (m 5 C) has been reported to regulate tumor progression, including PAAD progression. However, a comprehensive analysis of m 5 C regulators in PAAD is lacking.    Methods  In the present study, PAAD datasets were obtained from the Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and ArrayExpress databases. The expression pattern of m 5 C regulators were analyzed and patients were divided into different m 5 C clusters according to consensus clustering based on m 5 C regulators. Additionally, m 5 C differentially expressed genes (DEGs) were determined using Limma package. Based on m 5 C DEGs, patients were divided into m 5 C gene clusters. Moreover, m 5 C gene signatures were derived from m 5 C DEGs and a quantitative indicator, the m 5 C score, was developed from the m 5 C gene signatures.    Results  Our study showed that m 5 C regulators were differentially expressed in patients with PAAD. The m 5 C clusters and gene clusters based on m 5 C regulators and m 5 C DEGs were related to immune cell infiltration, immune-related genes and patient survival status, indicating that m 5 C modification play a central role in regulating PAAD development partly by modulating immune microenvironment. Additionally, a quantitative indicator, the m 5 C score, was also developed and was related to a series of immune-related indicators. Moreover, the m 5 C score precisely predicted the immunotherapy response and prognosis of patients with PAAD.    Conclusion  In summary, we confirmed that m 5 C regulators regulate PAAD development by modulating the immune microenvironment. In addition, a quantitative indicator, the m 5 C score, was developed to predict immunotherapy response and prognosis and assisted in identifying PAAD patients suitable for tailored immunotherapy strategies.

Comprehensive Analysis of 5-Methylcytosine (m5C) Regulators and the Immune Microenvironment in Pancreatic Adenocarcinoma to Aid Immunotherapy