In this study, we constructed a mRNA-LNP vaccine encoding human papillomavirus (HPV)-16 E7 protein (HPV mRNA-LNP), and aimed to (1) determine the optimal route of vaccination for inducing an efficacious overall and HPV-specific CD8+ T cell immune responses; (2) evaluate its anti-tumor effects in HPV-positive oropharyngeal squamous cell carcinoma (OPSCC); (3) systematically demonstrate its influence on the immune landscape and functional commitment of CD8+ T cells; (4) investigate whether its combination with immune checkpoint blockades could further enhance the anti-tumor efficiency. This evidence concerns the gene CD8A and oropharynx squamous cell carcinoma.