ATP (adenosine triphosphate) and HMGB1 (high mobility group box 1 protein) are key players in treatments that induce immunogenic cell death (ICD). However, conventional therapies, including radiotherapy, are often insufficient to induce ICD. In this study, we explore a strategy using nanoparticle-loaded macrophages as a source of ATP and HMGB1 to complement radiation-induced intrinsic and adaptive immune responses. To this end, we tested three inorganic particles, namely, iron oxide nanoparticles (ION), aluminum oxide nanoparticles (AON), and zinc oxide nanoparticles (ZON), in vitro with bone marrow-derived dendritic cells (BMDCs) and then in vivo in syngeneic tumor models. Our results showed that ION was the most effective of the three nanoparticles in promoting the secretion of ATP and HMGB1 from macrophages without negatively affecting macrophage survival. Secretions from ION-loaded macrophages can activate BMDCs. Intratumoral injection of ION-loaded macrophages significantly enhanced tumor infiltration and activation of dendritic cells and cytotoxic T cells. Moreover, exogenous ION macrophages can enhance the efficacy of radiotherapy. In addition, direct injection of ION can also enhance the efficacy of radiotherapy, which is attributed to ION uptake by and stimulation of endogenous macrophages. Instead of directly targeting cancer cells, our strategy targets macrophages and uses them as a secretory source of ATP and HMGB1 to enhance radiation-induced ICD. Our research introduces a new nanoparticle-based immunomodulatory approach that may have applications in radiotherapy and beyond.