Repurposing Antifungal Drugs for Oral Cancer Treatment: Mechanistic Insights and Clinical Potential—A Narrative Review

A bstract Objectives: Oral squamous cell carcinoma (OSCC) continues to pose significant therapeutic challenges due to high recurrence rates and treatment-related toxicity. Drug repurposing offers an accelerated, cost-effective pathway to discover novel therapeutic indications for established medications. This narrative review evaluates the mechanistic rationale and clinical potential of repurposing antifungal agents, such as azoles and allylamines, as adjuvant therapies for OSCC. Methods: A comprehensive literature search was performed across PubMed and Scopus (up to November 14, 2025). Studies were selected based on their focus on antifungal-mediated inhibition of OSCC growth and metastasis. Methodological quality was assessed using the Scale for the Evaluation of Narrative Review Articles. Results: Antifungal agents, particularly itraconazole and terbinafine, exhibit potent antitumor activity by targeting key oncogenic pathways, including the Sonic Hedgehog (SHH) and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin signaling axes. Preclinical evidence indicates that these agents induce apoptosis, inhibit angiogenesis, and sensitize OSCC cells to standard chemotherapy and radiotherapy. Specifically, itraconazole shows promise in treating SHH-high tumors, while terbinafine reduces tumor proliferation through antiangiogenic mechanisms. Conclusions: Antifungal drugs represent a biologically viable and resource-efficient strategy for enhancing OSCC treatment outcomes. To maximize clinical translation, future research must prioritize the development of nanoformulations and liposomal azoles to overcome existing bioavailability limitations.