Tumor antigen vaccination represents an appealing approach for cancer but has failed to materialize as oncologic standard of care. To understand long-term vaccine efficacy, we conducted a retrospective analysis of patients with human epidermal growth receptor 2+ (HER2+) breast cancer who received HER2-targeting vaccines and survived for >18 years. PBMC analysis revealed HER2-specific CD27+ memory CD4 and CD8 T cells, suggesting that CD27 signaling supports long-term immune memory. In human CD27 transgenic mice, combining HER2 vaccination with anti-CD27 agonism enhanced HER2-specific responses, particularly long-lived CD4 memory T cells. Murine models demonstrated ~40% tumor regression with combined therapy compared with vaccine alone (~6%). Additional scRNA-seq analysis identified CD4 T cells with a distinct gene expression profile, and depletion/adoptive transfer studies validated that CD4 T cells were essential for this effect. These findings suggest that CD27 agonism enhances vaccine-induced antigen-specific CD4 T cell responses, enabling durable antitumor immunity not entirely dependent on CD8 T cells.