Cancer cells can secrete exosomes under various stressful conditions, whose functions are involved in the delivery of various biologically active materials into host cells and/or modulation of host immune responses. Therefore, an improved understanding of the immunological interventions that stress-induced tumor exosomes have may provide novel therapeutic approaches and more effective vaccine designs. Here, we confirmed the phenotypical and functional alterations of dendritic cells (DCs), which act as a bridge between the innate and adaptive arms of immunity, following non-irradiated (N-exo) and gamma-irradiated melanoma cancer cell-derived exosome (G-exo) stimulation, and evaluated the N-exo- and G-exo-stimulated DCs as therapeutic cancer vaccine candidates. We demonstrated that G-exo-stimulated DCs result in DC maturation by the upregulation of surface molecule expression, pro-inflammatory cytokine release, and antigen-presenting ability, and the downregulation of endocytic capacity. In addition, these cells promoted T cell proliferation and the generation of T helper type 1 (Th1) and interferon (IFN)-γ-producing CD8⁺ T cells. However, N-exo-stimulated DCs induced semi-mature phenotypes and functions, eventually inhibiting T cell proliferation, decreasing IFN-γ, and increasing IL-10-producing CD4⁺ T cells. In addition, although N-exo and G-exo stimulations showed similar levels of antigen-specific IFN-γ production, which served as tumor antigen sources in melanoma-specific T cells, G-exo-stimulated DC vaccination conferred a stronger tumor growth inhibition than N-exo-stimulated DC vaccination; further, this was accompanied by a high frequency of tumor-specific, multifunctional effector T cells. These results suggest that gamma irradiation could provide important clues for designing and developing effective exosome vaccines that can induce strong immunogenicity, especially tumor-specific multifunctional T cell responses.