Hafnium Metal–OrganicFramework-Based GlutamineMetabolism Disruptor For Potentiating Radio-Immunotherapy in <i>MYC</i>-Amplified Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) with <i>MYC</i> oncogene amplification remains a serious challenge in clinical practice. Recent advances in comprehensive treatment strategies, particularly the combination of radiotherapy and immunotherapy, offer new hope. To further improve efficacy while lowering radiation doses, nanopharmaceuticals based on high-Z elements have been extensively studied in radio-immunotherapy. In this work, a hafnium-based metal–organic framework (Hf-MOF), UiO-66-Hf(2OH)-CB-839/BSO@HA (UiO-66-Hf(2OH)-C/B@HA), was designed to codeliver telaglenastat (CB-839) and buthionine sulfoximine (BSO), which synergistically inhibited glutamine metabolism and alleviated tumor hypoxia. Further modification with hyaluronic acid (HA) enhanced tumor targeting, ultimately strengthening the efficacy of radiotherapy in <i>MYC</i>-amplified HCC. Beyond increasing reactive oxygen species (ROS) generation, promoting DNA damage, and inducing tumor apoptosis, more importantly, UiO66-Hf(2OH)-C/B@HA triggered immunogenic cell death (ICD), driving the antitumor immune response. Combination with immune checkpoint blockade (ICB) further enhanced the efficacy, accompanied by increased infiltration of T cells with high granzyme B expression (GZMB⁺ T cells) within the tumor microenvironment (TME). In the orthotopic HCC model, established with <i>MYC</i>-amplified tumor cells, intravenous administration of UiO66-Hf(2OH)-C/B@HA significantly potentiated the efficacy of radio-immunotherapy, resulting in superior tumor regression. In summary, our study provides insights into the design of Hf-MOF for radio-immunotherapy and proposes a promising therapeutic approach for <i>MYC</i>-amplified HCC.