Synergistic Integration of Hafnium Oxide Nanoradiosensitizers and Immune Checkpoint Inhibition for Enhanced Cancer Therapy

Abstract

Locally injected hafnium oxide (HfO₂) shows promising efficacy in radiotherapy (RT) for soft tissue sarcomas. Although it has advanced to clinical trials for solid tumors, this approach remains limited by its invasiveness and poor efficacy against metastatic disease. To address this, we developed ultrasmall (5 nm) OA/HfO₂(OH) via solvothermal synthesis and coated them with DSPE-PEG₂₀₀₀, forming HfO₂@PEG (OHP) to impart systemic circulation and tumor targeting via the enhanced permeability and retention (EPR) effect. As a highly efficient radiosensitizer, OHP enhances RT at a low dose (4 Gy) by significantly increasing intracellular reactive oxygen species (ROS) and oxidative damage, effectively killing cancer cells. In 4T1 cells, OHP combined with RT raised ROS levels more than 10-fold compared to RT alone. Importantly, this process also triggers a potent immune response by activating dendritic cells (DCs) and enhancing antigen presentation, thereby initiating a systemic attack against tumors. Combining OHP-enhanced RT with αPD-L1 antibody therapy yields strong synergistic outcomes, effectively shrinking primary tumors and suppressing distant metastases. Tumor weights in the combination group were significantly lower than in the RT group, with primary and distant tumors reduced to approximately one-sixth and one-fifth, respectively. OHP can be gradually metabolized and excreted, mitigating risks of long-term accumulation and chronic toxicity. This work establishes a systemically deliverable hafnium-based platform with strong clinical translation potential. It proposes a novel strategy to transform traditional local RT into a systemic therapy that activates antitumor immunity, thereby paving the way for innovative treatment models that effectively merge radiosensitization with immunotherapy.

Keywords

hafnium oxide / immunogenic cell death / programmed death-ligand / radiosensitizers

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