In this work, we showed for the first time that targeted delivery of the diphtheria cytotoxic domain to CXCR4-overexpresing human HNSCC via the T22-DITOX-H6 nanotoxin effectively eliminates the cancer cells present in the invasive front of primary tumors, thus demonstrating a potent anti-invasive effect. Here, CXCR4 is linked to cancer.