• Identifies a novel class of cancer-specific bivalent promoters (CSBPs) with low H3K27me3 and high H3K4me3, enabling active transcription of oncogenic programs.
• CSBPs are generated during cell state transition via PRC2.1 binding and de novo PRC2.2 recruitment, linking epigenetic reprogramming to cancer stem cell maintenance.
• Disrupting CSBP bivalency increases H3K4me3 and hyperactivates these promoters, inhibiting CSC clonal expansion and tumorigenesis, offering a potential therapeutic strategy.
• Provides a system-level framework to resolve the paradox of active bivalent genes in cancer and highlights phenotypic plasticity as a target for cancer therapy.