Despite advancements in immune checkpoint blockade (ICB) therapies for treating various tumors, the immunosuppressive environment in oral squamous cell carcinoma (OSCC) significantly limits therapeutic efficacy. Tumor vaccines, which offer great potential for cancer immunotherapy, still face challenges like potential mutation risks, rapid elimination, and low in vivo delivery efficiency. In this study, we fabricate an immunostimulatory nanovaccine using tetrahedral framework nucleic acids (tFNAs) as a carrier for stable and efficient delivery of CpG oligonucleotide. Then an intensive tumor immunotherapeutic strategy by combining tFNA-CpG nanovaccine with PD-1 inhibitor is used in OSCC tumor-bearing mice. Intravenous administration of the tFNA-CpG nanovaccine effectively activates the antigen-presenting cells (APCs), resulting in an increased proportion of M1-like macrophages and mature dendritic cells, accompanied by heightened production of inflammatory cytokines IL-1 beta, IL-12, and IL-6. When combined with ICB therapy, the anti-PD-1 drug inhibits the PD-1/PD-L1 interaction within tumor microenvironment. Subsequently, the APCs activated by tFNA-CpG facilitate the phenotypic differentiation of T cells, resulting in a substantial boost in infiltration of cytotoxic T cells (expressing IFN-gamma and Granzyme B) in both lymph nodes and tumor tissues, thereby executing a potent antitumor effect and inhibiting the progression of OSCC tumors in C3H mouse. Therefore, this study presents an attractive approach to overcoming current ICB limitations in OSCC immunotherapy and provides new avenues for future clinical practice.