In this study (which rationale is summarized in Supplementary Fig. 8), we report for the first time that targeted toxin delivery to CXCR4-overexpresing (CXCR4+) human HNSCC cells, achieved by the T22-PE24-H6 and T22-DITOX-H6 nanotoxins, activates caspase-3/GSDME-dependent pyroptosis in CXCR4+ cancer cells. Here, CASP3 is linked to head and neck squamous cell carcinoma.