Reengineering the Tumor Oxygen Microenvironment in Radiotherapy to Enhance T‐Cell Function for Radio‐Immunotherapy

Abstract Analyzing the relationship between tumor O 2 microenvironment (TOME) and immune microenvironment during radiotherapy and regulating it will provide new insights into the combination of radiotherapy and immunotherapy. In the experiments, it is observed that the exacerbation of tumor hypoxia after radiotherapy activated the HIF pathway, which, in turn, led to T‐cell exhaustion by upregulating PD‐L1 expression in the tumor and promoting the infiltration of MDSCs. To address this, a manganese ion‐doped Au–Pt nanozyme‐coated O 2 modulator (Mn‐Nz‐M) is designed and prepared to reengineer the TOME. First, the high catalase activity of Mn‐Nz‐M efficiently generated O 2 at the tumor‐site, modulating the TOME and improving radiotherapy efficacy. More importantly, studies in vitro and in vivo showed that Mn‐Nz‐M‐mediated improvement of TOME can reverse PD‐1 + T cell exhaustion post radiotherapy and activate T cell function. Additionally, the Mn 2+ released from Mn‐Nz‐M can simultaneously amplify the cGAS‐STING pathway to activate NK cells for anti‐tumor activity. This reengineering strategy of the TOME for radio‐immunotherapy not only eliminates primary solid tumors but also inhibits tumor metastasis, providing new insights and potential therapeutic targets for enhancing the interaction between radiotherapy and immunotherapy.