Introduction: Mucosal tumors, such as human papillomavirus (HPV)-driven head and neck carcinomas (HNC), present distinct therapeutic challenges due to their anatomical site and immunological environment. While most therapeutic cancer vaccines emphasize T cell responses, emerging evidence highlights a pivotal role for B cells in antitumor immunity. The contribution of B cells in mucosal tumors, however, remains poorly understood. Methods: We evaluated an intranasally delivered, tetravalent virus-like particle (VLP) nanovaccine, Qβ-HPVag, which presents elongated HPV16 E6/E7 epitopes and includes a TLR-9 agonist for self-adjuvancy. Using a cold, orthotopic HPV⁺ HNC mouse model, we assessed local and systemic immune responses following mucosal immunization. Results: Qβ-HPVag significantly reduced tumor burden and enhanced infiltration and function of cytotoxic CD8⁺ T cells within the tumor microenvironment. Critically, B cell depletion abrogated the vaccine’s efficacy, revealing a central role for B cells in mediating antitumor responses. Vaccination led to the expansion of tumor-infiltrating memory B cells, plasmablasts, and IgA⁺ B cells, and induced robust systemic HPV-specific IgG. Notably, vaccine efficacy was lost in C3-deficient mice, implicating complement activation as a key mediator of humoral immunity. Conclusion:Our findings demonstrate that effective mucosal vaccination against HPV⁺ HNC requires coordinated activation of both B and T cells. This study establishes B cells and complement pathways as critical components of next-generation therapeutic vaccine strategies for mucosal cancers.