Background: Pancreatic ductal adenocarcinoma (PDAC) is recognized as an exceptionally aggressive malignancy with limited treatment options. Radiotherapy, particularly creotactic body radiotherapy, plays a vital role in cancer management but faces challenges due to the complex microenvironment of tumors and intrinsic resistance mechanisms. Materials and Methods: Transcriptomic data from PDAC tissue samples were analyzed pre- and post-stereotactic body radiotherapy to identify variations in the expression of lncRNAs and mRNAs. Additionally, bioinformatics approaches were used to explore their interactions, focusing on the effects on p53-mediated apoptosis and immune cell dynamics, and to assess their potential as biomarkers for radiotherapy outcomes. Results: Genes linked to p53-driven apoptosis and DNA damage response showed significant upregulation after stereotactic body radiotherapy, highlighting the cytotoxic effects of radiotherapy. Conversely, immune-related genes were downregulated, indicating an immunosuppressive tumor microenvironment following radiotherapy. Meanwhile, co-expression analysis revealed a regulatory network between lncRNAs and mRNAs that influence radiotherapy-induced cytotoxicity and immunosuppression. Lastly, a risk model was constructed by incorporating three mRNAs (HSPA1L, MT-CYB, PMAIP1) and five lncRNAs (AC018816.3, RP11-147L13.2, CTD-2651B20.6, RP11-422P24.10, AC067945.4) to predict radiotherapy outcomes. Conclusion: This study uncovers the intricate interaction between lncRNAs and mRNAs in PDAC, especially in the context of radiotherapy. Our results demonstrated that the lncRNA-mRNA network significantly impacts the tumor microenvironment and radiotherapy response by regulating pathways involved in cell death and immunosuppression. Thus, targeting this network could enhance radiotherapy efficacy and mitigate its immunosuppressive effects, offering novel strategies to improve the treatment outcomes of PDAC.
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