In conclusion, our results suggest that the therapeutic efficacy of systemic α-PD-1 immunotherapy of HPV+ oropharyngeal HNSCC, both in the case of primary and advanced metastatic disease (modeled here with mice harboring tumors in the flank and tongue) can be greatly enhanced by combining with additional T cell checkpoint-targeting antibodies such as α-CTLA-4 and/or through intratumoral delivery of STING activating agents to achieve near complete and durable tumor regression. Here, STING1 is linked to metastatic neoplasm.