Successful immunotherapy requires systemic activation of the immune system. Radio-immunotherapy has a synergistic effect, enhancing this activation, but still faces many challenges, requiring methods to further improve its efficacy. Interleukin 15 (IL-15) is considered a potential therapeutic agent because of its broad immunoregulatory activity. This study found that in various tumor-bearing mouse models, systemic immune activation mediated by memory T cells in secondary lymphoid organs was crucial after radio-immunotherapy and IL-15 played a key role in this process. Radio-immunotherapy stimulated the expression of IL-15Rα on macrophages in the tumor microenvironment. When macrophages were depleted, the IL-15 levels in the tumor microenvironment and spleen tissues significantly decreased. Co-culture models confirmed that radio-immunotherapy enhanced the anti-tumor immune response by activating macrophages to secrete IL-15. Applying IL-15 significantly enhances the effects of radio-immunotherapy, stimulating systemic immune activation and providing long-term memory effects and tumor protection. Under co-culture conditions, IL-15 combined with radio-immunotherapy stimulated the proliferation of CD8