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. Here, TP63 is linked to head and neck squamous cell carcinoma.