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Background Novel approaches are needed to improve the clinical outcome and prolong survival in relapsed head and neck squamous cell carcinoma (HNSCC) cases unrelated to HPV infection which often present with a poor prognosis and have poor long-term responses to immune checkpoint blockade. This study evaluated the chemokine receptors CXCR1 and CXCR2 as potential novel targets for the treatment of HPV-negative HNSCC and combination therapy strategies for more effective treatment of this disease. Overexpression of CXCR1, CXCR2, and their ligands CXCL1/2/3/5/6/7/8 in several tumor types has been shown to promote mechanisms of tumor progression while subsequently driving resistance to chemotherapy and immunotherapy. Resistance mechanisms related to CXCR1/2 receptor-associated signaling pathways include increasing tumor angiogenesis, inducing tumor cellular plasticity leading to increased tumor cell migration, invasiveness, and resistance to cell death, and chemoattracting PMN-MDSC to the tumor microenvironment.Methods Expression of IL-8, CXCR1, and CXCR2 was investigated in HNSCC tissues and human cell line models. Inhibition of CXCR1/2 with the clinical stage, small molecule inhibitor, SX-682, was evaluated in vitro and in vivo using human xenografts and murine models of HNSCC, both as a monotherapy and in combination with the taxane chemotherapy, docetaxel.Results Our initial analysis of HNSCC tissues via RNA in situ hybridization revealed that high levels of IL-8, CXCR1, and CXCR2 expression were present in HPV-negative compared to HPV-positive HNSCC tumors or cell lines. Treatment of HPV-negative HNSCC cell lines in vitro with a CXCR1/2 inhibitor sensitized the tumor cells to the cytotoxic activity of docetaxel. In addition, in vivo, treatment of HNSCC xenograft models with the combination of CXCR1/2 inhibition plus docetaxel led to strong anti-tumor control resulting in tumor cures. This phenomenon was associated with an increase of microRNA-200c and a decrease of tubulin beta-3, a protein involved in resistance to microtubule-targeting chemotherapies. Additionally, in vivo treatment of a murine syngeneic model of HNSCC with CXCR1/2 inhibition plus docetaxel led to potent anti-tumor efficacy through a simultaneous decrease in suppressive CXCR2 + PMN-MDSC and an increase in cytotoxic CD8+ T cells in combination therapy treated tumors compared to the controls.Conclusions This study reports, for the first time, mechanistic findings through which the combination of CXCR1/2 inhibition and docetaxel chemotherapy exhibits synergy in models of HPV-negative HNSCC. These findings provide rationale for the use of this novel combination approach to treat HPV-negative HNSCC patients and for future combination studies of CXCR1/2 inhibition, docetaxel, and immune-based therapies.