Emerging evidence suggests that DNA methylation affects transcriptional regulation and expression perturbations of long non-coding RNAs (lncRNAs) in cancer. However, a comprehensive investigation into the transcriptional control of DNA methylation-mediated dysregulation of transcription factors (TFs) on lncRNAs has been lacking. Here, we integrated the transcriptome, methylome, and regulatome across 21 human cancers and systematically identified the transcriptional regulation of DNA methylation-mediated TF dysregulations (DMTDs) on lncRNAs. Our findings reveal that TF regulation of lncRNAs is significantly impacted by DNA methylation. Comparative analysis of DMTDs on mRNAs revealed a conserved pattern of TFs involvement. Pan-cancer Methylation TFs (MethTFs) and Methylation LncRNAs (MethLncRNAs) were identified, and were found to be closely associated with cancer hallmarks and clinical features. In-depth analysis of co-expressed mRNAs with pan-cancer MethLncRNAs unveiled frequent disruptions in cancer immunity, particularly in the context of inflammatory response. Furthermore, we identified five immune-related network modules that contribute to immune cell infiltration in cancer. Immune-related subtypes were subsequently classified, characterized by high levels of immune cell infiltration, expression of immunomodulatory genes, and relevant immune cytolytic activity score, major histocompatibility complex score, response to chemotherapy, and prognosis. Our findings provide valuable insights into cancer immunity from the epigenetic and transcriptional regulation perspective.
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