Gadolinium-based ultra-small nanoparticles augment radiotherapy-induced T-cell response to synergize with checkpoint...

Radiotherapy suffers from its high-dose radiation-induced systemic toxicity and radioresistance caused by the immunosuppressive tumor microenvironment. Immunotherapy using checkpoint blocking in solid tumors shows limited anticancer efficacy due to insufficient T-cell infiltration and inadequate systemic immune responses. Activation and guiding of irradiation by X-ray (AGuIX) nanoparticles with sizes below 5 nm have entered a phase III clinical trial as efficient radiosensitizers. This study aimed to develop a unique synergistic strategy based on AGuIX-mediated radiotherapy and immune checkpoint blockade to further improve the efficiency for B16 tumor therapy. AGuIX exacerbated radiation-induced DNA damage, cell cycle arrest, and apoptosis on B16 cells. More importantly, it could efficiently induce the immunogenic cell death of irradiated B16 tumor cells, and consequently trigger the maturation of dendritic cells and activation of systemic T-cell responses. Combining AGuIX-mediated radiotherapy with programmed cell death protein 1 blockade demonstrated excellent synergistic therapeutic effects in both bilateral and metastatic B16 tumor models, as indicated by a significant increase in the infiltration of effector CD8⁺ T cells and effective alleviation of the immunosuppressive tumor microenvironment. Our findings indicate that the synergy between radiosensitization and immunomodulation provides a new and powerful therapy regimen to achieve durable antitumor T-cell responses, which is promising for cancer treatment.