Combining High-Z Sensitized Radiotherapy with CD73 Blockade to Boost Tumor Immunotherapy

Radiation therapy (RT) has the capacity to induce immunogenic death in tumor cells, thereby potentially inducing in situ vaccination (ISV) to prime systemic antitumor immune responses. However, RT alone is often faced with various limitations during ISV induction, such as insufficient X-ray deposition and an immunosuppressive microenvironment. To overcome these limitations, we constructed nanoscale coordination particles AmGd-NPs by self-assembling high-Z metal gadolinium (Gd) and small molecular CD73 inhibitor AmPCP. Then, AmGd-NPs could synergize with RT to enhance immunogenic cell death, improve phagocytosis, and promote antigen presentation. Additionally, AmGd-NPs could also gradually release AmPCP to inhibit CD73's enzymatic activity and prevent the conversion of extracellular ATP to adenosine (Ado), thereby driving a proinflammatory tumor microenvironment that promotes DC maturation. As a result, AmGd-NPs sensitized RT induced potent in situ vaccination and boosted CD8⁺ T cell-dependent antitumor immune responses against both primary and metastatic tumors, which could also be potentiated by immune checkpoint inhibitory therapy.