In summary, we propose a novel malignant cell-mediated mechanism of ferroptosis resistance: high expression of TP63 in TP63+ SLC7A5+ HNSCC subpopulation upregulates SLC7A5 expression through transcriptional regulation, inhibits ferroptosis in HNSCC cells, maintains the cellular homeostatic balance, and promotes tumor resistance to immunotherapy. The gene discussed is TP63; the disease is neoplasm.