ABT-263, a drug that eliminates senescent cells by blocking anti-apoptotic proteins Bcl-xL and activating Bax, showed dramatically different effects in two head and neck cancer cell lines based on their CXCR2 receptor expression patterns. In Cal33 cells, ABT-263 downregulated CXCR2 and successfully sensitized tumors to radiation, reducing both cell viability and clonogenic survival. However, in UPCI:SCC040 cells, the drug paradoxically increased CXCR2 expression, maintaining radioresistance despite reduced viability. This differential response illuminates a critical gap in precision oncology approaches to head and neck cancers, which remain among the most treatment-resistant malignancies. The finding that concurrent CXCR2 inhibition could restore radiosensitization in resistant cells suggests a potential combination therapy strategy. This represents more than an incremental advance—it reveals how chemokine signaling networks can hijack senolytic interventions, potentially explaining why promising anti-aging drugs like ABT-263 show inconsistent results in cancer trials. For the broader longevity field, this underscores the complexity of targeting senescence therapeutically, as the same pathways that promote healthy aging may interact unpredictably with existing disease states.