Magnolol as a Radiotherapy Enhancer in Oral Squamous Cell Carcinoma: Targeting the EGFR/NF‐κB Pathway and Immune Modulation

Oral cancer, particularly oral squamous cell carcinoma (OSCC), often exhibits resistance to standard treatments like surgery, chemotherapy, and radiation therapy (RT). Magnolol, a bioactive compound from the bark of Magnolia officinalis, is recognised for its anti-inflammatory, antioxidant, antimicrobial, and antitumor properties. This study aims to explore magnolol's potential to enhance the therapeutic efficacy of RT in oral cancer models. Using MOC1-bearing animals, we evaluated the combined effect of magnolol and RT. The results showed that magnolol significantly suppressed tumour growth, delayed progression, and reduced tumour weight compared to control groups. Immune profiling revealed that magnolol plus RT promoted positive immune regulation by increasing M1 macrophages, dendritic cells, and activated cytotoxic T cells, while suppressing negative regulators like myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). Immunohistochemical analysis also demonstrated enhanced activation of apoptosis-related pathways including the cleavage of caspase-3, -8, and -9. Furthermore, the combination of magnolol and RT did not induce significant toxicity, as evidenced by stable body weight, normal tissue pathology, and normal liver and kidney function markers. Notably, the phosphorylation levels of EGFR and NF-κB were significantly reduced in the magnolol plus RT group, similar to the effects seen with erlotinib plus RT. In conclusion, these findings highlight magnolol's ability to enhance the efficacy of RT in oral cancer by targeting the EGFR/NF-κB axis, inducing apoptosis, and modulating immune responses, presenting a promising therapeutic strategy for OSCC.