In this study, we employed ABT-263 to overcome the therapy-induced resistance in HNSCC cells and uncovered a link to chemokine signaling.<h4>Methods</h4>The HNSCC cell lines Cal33 and UPCI:SCC040 were treated with a combination of ABT-263 and photon irradiation, followed by functional and mechanistic assays assessing viability, apoptosis, senescence, secreted proteins, clonogenic survival, and DNA repair.<h4>Results</h4>Functionally, ABT-263 induced apoptosis via impeding Bcl-xL and activating Bax. The gene discussed is BCL2L1; the disease is head and neck squamous cell carcinoma.