There is a high rate of recurrence (>50%) in patients diagnosed with head and neck squamous cell carcinoma (HNSCC) following multimodality treatment. This poor prognosis is especially pronounced in a subset of head and neck cancers i.e. oral cavity (OSCC). Anti-PD1 checkpoint inhibitor immunotherapy is an option for recurrent/metastatic OSCC; however, clinical response is <20%. Chemotherapy resistant tumors and cell lines overexpress CXCL12 which promotes chemo-resistance, aggressive growth and immune evasion. Concurrent with CXCR4 overexpression, recurrent OSCC shows increased PD-1, presence of CD25+CD4+Tregs and CD8+ T cell infiltration. These features suggest a complex immunosuppressive tumor microenvironment (TME) that may require a multipronged treatment for reactivation. We hypothesize that the CXCR4 and PD-1 pathways work in parallel to increase immune suppression, decrease immune cell activity and augment tumor resistance to treatment. We therefore implemented a novel approach to concurrently target these two independent pathways. We have developed cisplatin resistant variants of mouse oral cancer cell lines (MOC1 and MOC2) to evaluate combined CXCR4 and PD-L1 blockade (AMD 3100 and Nivolumab). We validated the expression of both CXCR4 and PD-L1 in these cell lines. shRNA knockdown of CXCR4 provided a direct demonstration of its significance in the PD-L1 immune checkpoint inhibitor response in OSCC. Co-culture of these tumor cell lines with CD4+ and CD8+ mouse T cells provided a system in which to assay the effects of immunotherapy on tumor cell viability and proliferation. This model was used to determine whether CXCR4 inhibition could enhance anti-PD-L1 efficacy. Combinatorial blockade of both pathways provided better outcomes relative to anti-PD-L1 treatment and extended our understanding of immunotherapy resistance.