Methylation of the Cg12712415 Locus Suppresses TAK1 Expression to Mediate Immune Paralysis in Severe Pneumonia

Severe pneumonia lethality often arises not from excessive inflammation, but from subsequent immune system "paralysis" (immunoparalysis), a clinical challenge lacking specific biomarkers and effective therapies. Our study addressed this by identifying key epigenetic checkpoints driving immunoparalysis. Herein, we identify that DNA methylation at the Cg12712415 locus acts as an epigenetic switch to distinguish and predict secondary immunoparalysis in severe pneumonia patients. Mechanistically, DNMT3A specifically catalyzes this methylation, silencing transcription of the critical kinase TAK1 by blocking RNA polymerase II binding. TAK1 loss impairs monocyte/macrophage functions, disrupts intercellular crosstalk, induces CD8⁺ T cell exhaustion and regulatory T cell expansion, and causes systemic immunosuppression. Importantly, macrophage-derived exosome-mediated TAK1 delivery reversed immunoparalysis and improved survival in animal models. Our findings establish the "DNMT3A–Cg12712415–TAK1" axis as a novel regulatory pathway, provide a new immunoparalysis biomarker, and lay the foundation for an epigenetic-based targeted therapy.