Hmno₂-Mediated Ldrt Restores Cell Stiffness To Activate Nk Cell

Tumor immune escape is a critical factor in malignant tumor progression. The hypoxic tumor microenvironment and the enrichment of GSH are not only core mechanisms underlying tumor resistance to ROS-induced damage but also key contributors to immune evasion. Low-dose radiotherapy (LDRT) can enhance the efficacy of tumor immunotherapy by converting "cold tumors" into "hot tumors." This study aims to investigate the mechanism by which HMnO₂ nanoparticles combined with LDRT improve the tumor immune microenvironment and enhance antitumor immunotherapy in OSCC. HMnO₂ were synthesized and characterized to confirm their successful preparation and tumor microenvironment responsiveness. In vitro experiments evaluated the cytotoxicity of HMnO₂-mediated LDRT, while AFM, lipid raft and cytoskeletal staining were employed to assess its effects on tumor cell stiffness. In vivo experiments investigated the impact on tumor growth. Single-cell RNA sequencing (scRNA-seq) was performed to analyze tumor cell stiffness changes and NK cell-mediated immune responses. HMnO₂-mediated LDRT synergistically alleviated tumor hypoxia, depleted GSH, and amplified oxidative stress in tumor tissues. Additionally, it modulated tumor cell stiffness, impairing their ability to evade mechanical killing by NK cells. In vivo experiments and scRNA-seq confirmed that HMnO₂-mediated LDRT regulated tumor cell stiffness, promoted NK cell recruitment, and enhanced their cytotoxic function. HMnO₂-mediated LDRT significantly enhances antitumor immune responses by ameliorating hypoxia, depleting GSH, modulating tumor cell stiffness, and activating NK cell function. This study provides a novel radioimmunotherapy strategy for cancer treatment and opens new avenues for improving the efficacy of immunotherapy.