Oral squamous cell carcinoma (OSCC), which accounts for over 90% of malignancies in the oral cavity, is associated with a poor prognosis, with a 5-year mortality rate reaching of up to 44%. The incidence of OSCC continues to rise annually, and current treatment typically involves a combination of surgical resection, chemotherapy, and radiotherapy. In recent years, there has been growing interest in targeted therapies that exploit molecular markers involved in tumor growth and metastasis. Among these targets, immune checkpoint molecules such as programmed cell death 1 receptor (PD-1) and its ligand, programmed cell death-ligand 1 (PD-L1), have garnered significant attention. Therapies that inhibit these immune checkpoints have been approved for various malignancies, offering new avenues for treatment. Pembrolizumab (Keytruda), a PD-1 immune checkpoint inhibitor, has emerged as a promising therapuetic option for OSCC. However, its clinical response rate in OSCC patients remains below 20%, highlighting the need for combination strategies to enhance therapeutic efficacy. One such approach involves non-thermal plasma (NTP), a novel modality that selectively induces apoptosis in cancer cells. In this study, the authors evaluated the combined effect of Keytruda and NTP in an OSCC xenograft mouse model. The combination therapy demonstrated the tendency of suppressed tumor growth compared to Keytruda monotherapy. This effect was accompanied by increased apoptosis, as indicated by elevated cleaved caspase-3 expression, and reduced proliferation, as shown by decreased Ki-67 expression. Although preliminary, these findings may support the potential clinical application of Keytruda-NTP combined therapy as a novel treatment strategy for OSCC.