This study reports two major mechanistic findings through which CXCR1/2 inhibition plus docetaxel chemotherapy exhibit synergy in models of HPV-negative HNSCC: (a) a tumor cell intrinsic mechanism in which CXCR1/2 inhibition modulates miR-200c and tubulin beta-3 expression to uniquely sensitize cancer cells to the cytotoxic activity of docetaxel, and (b) an immune-mediated mechanism characterized by enhanced T-cell activation and reduced suppressive myeloid cells, ultimately promoting anti-tumor immunity. Here, TUBB3 is linked to head and neck squamous cell carcinoma.