The use of immune checkpoint modulation to enhance anti-tumor immunity while minimizing immune suppressive responses within tumors has proven to be highly successful for the treatment of many cancers, however, toxic side effects and financial constraints limit its wider clinical application. Using preclinical models of human papillomavirus (HPV) cancers, we tested whether vaccination employing adjuvants with potent immune enhancing potentials and clinical safety profiles could alleviate this concern for achieving anti-tumor efficacy.  Since most HPV tumors occur at mucosal tissues, we incorporated mucosal intranasal vaccination with E6 and E7 peptides representing tumor-specific antigens to treat vaginal HPV+ TC-1 tumors. We observed that vaccine formulation incorporating the CpG-containing oligo-deoxynucleotide (CpG-ODN), which activates antigen-presenting cells (APCs) through the TLR9 pathway, was effective in reducing tumor growth relative to untreated controls, however, complete and durable regression in the majority of mice required supplementing the vaccine with the α-galactosylceramide (αGalCer) adjuvant to enhance APCs activation through the engagement of natural killer T (NKT) cells.  The improved efficacy achieved by incorporating aGalCer adjuvant in addition to CpG-ODN correlated with doubling of CD8 T cells exhibiting enhanced cytotoxic potential (54% increase in granzyme B) within the tumor.  Furthermore, the ratio of CD8 T cells to regulatory T cells was augmented by 84% in mice treated with the combination adjuvants versus CpG-ODN alone.  Intranasal vaccination delivering α-GalCer, to allow for anergy-free stimulation of NKT cells and the alternate licensing of dendritic cells, which complements the classical licensing afforded by the CpG-ODN signaling to attract diverse populations of CD8+ CTL, preferentially to the female reproductive site, is the hypothesized mechanism underlying the superior efficacy of the HPV vaccine incorporating the two adjuvants.