Abstract
Bmi1+ tumor cells act as cancer stem cells (CSCs) driving relapse and therapy resistance in head and neck squamous cell carcinoma (HNSCC). Although BMI1 inhibitors reduce CSCs, combined cisplatin treatment targeting non-stem tumor cells is more effective in eliminating CSCs. Non-stem tumor cells may revert to CSCs post-treatment. However, in vivo evidence and underlying mechanisms remain unclear. Here, we demonstrate that BMI1 inhibitors induce temporary tumor regression followed by relapse. Lineage tracing reveals that keratin 16-marked non-stem tumor cells revert to Bmi1+ CSCs, which drive compensatory tumor growth after BMI1 targeting therapy. Mechanistically, BMI1 inhibitors activate DNA damage/nuclear factor κB (NF-κB) signaling and inflammatory cytokine secretion, subsequently stimulating myelocytomatosis viral oncogene homolog (MYC) expression in non-stem tumor cells to promote the reversion process. Genetic and pharmacological inhibition of MYC synergizes with BMI1 targeting, achieving sustained CSC eradication and relapse prevention. These findings provide insights into CSCs' plasticity and suggest dual BMI1/MYC blockade as an effective HNSCC treatment strategy.