Abstract: Background　Conventional treatments for oral squamous cell carcinoma (OSCC) present certain limitations. While microwave (MW) therapy provides the benefit of being minimally invasive, its clinical application is hindered by technical challenges, including non-uniform heat distribution, low targeting accuracy, and inadequate temperature control precision. Objective　To investigate the application value of high-entropy alloy nanoparticles (HEA NPs) as novel microwave sensitizing materials, and leverage their unique microwave sensitizing properties to enhance the efficacy of microwave thermodynamic therapy for achieving precise ablation of OSCC. Methods　Multiple characterization techniques were employed to analyze the physicochemical properties of synthesized HEA NPs, including particle size distribution and surface charge determination. Microwave response performance testing was conducted to evaluate the microwave sensitizing effects and peroxidase-like (POD like) catalytic activity of the materials. Biological safety assessments were performed using a mouse fibroblast cell model (NCTC clone 929, L929), while microwave therapy experiments were carried out with human tongue squamous cell carcinoma cells (Centre Antoine Lacassagne, Cal-27). A systematic evaluation of the material's enhancement of microwave anti-tumor effects was conducted through multidimensional experiments, including cell viability assays, reactive oxygen species (ROS) level measurements, and calcium ion (Ca² ⁺) concentration analysis. Results　Performance characterization data revealed that HEA NPs had an average particle size of 69.5 nm and a surface zeta potential of -13 mV. They exhibited POD-like activity and demonstrated a pronounced microwave sensitization effect (P＜0.01). Cell experiments confirmed that the material maintains favorable biocompatibility while significantly enhancing the anti-tumor efficacy of microwave therapy (P＜0.01).Conclusion　This research indicates that HEA NPs, acting as a novel microwave sensitizer, offers a new avenue for research aimed at optimizing microwave therapy strategies for oral squamous cell carcinoma.