Protacs in oral cancer: degrading oncogenic drivers for next-generation therapy

Oral squamous cell carcinoma (OSCC) remains difficult to treat because of its intricate molecular profile, its limited responsiveness to conventional therapeutic approaches, and the challenge of targeting key oncogenic drivers with standard drugs. An emerging approach that addresses these limitations is the use of proteolysis-targeting chimeras (PROTACs), which shifts the focus from traditional inhibition of protein activity to the deliberate degradation of disease-associated proteins. PROTACs can eliminate oncogenic proteins like EGFR, STAT3, c-MYC, and anti-apoptotic regulators by hijacking the ubiquitin-proteasome system, many of which are essential for OSCC pathophysiology and are considered undruggable. This method provides a catalytic, sustained mechanism of action and overcomes the resistance arising from target overexpression, mutation, or signaling redundancy. Recent advances in PROTAC design, consisting of orally bioavailable degraders and tissue-directed delivery systems, highlight their translational capacity in epithelial tumors. PROTACs enable degradation of critical effectors involved in proliferation, immune evasion, and therapy resistance in OSCC. Hence, this review highlights how PROTAC technology addresses the current molecular targeting gaps in OSCC and outlines future directions for translating targeted protein degradation into clinical therapy.