Proteolysis‑targeting chimeras in oral squamous cell carcinoma: Current evidence, translational challenges and future...

Oral squamous cell carcinoma (OSCC) poses a significant clinical challenge due to its high recurrence rate, resistance to treatment and the functional morbidity associated with current therapies. Although proteolysis‑targeting chimeras (PROTACs) have emerged as a promising oncological platform, their application in oral cancer remains in the early stages, largely supported by preclinical data. The present review reconsiders PROTAC development from an OSCC‑specific perspective, rather than a generalized cross‑cancer framework. Key findings directly relevant to OSCC/head and neck squamous cell carcinoma are highlighted, distinguishing them from hypotheses extrapolated from other solid tumors. Biologically validated candidate targets for protein degradation are summarized, and delivery strategies are evaluated for their translational relevance to the oral cavity. Local transmucosal delivery, stimuli‑responsive activation and microneedle‑assisted locoregional administration are particularly promising for OSCC, as these approaches may enhance local selectivity while minimizing systemic exposure. This review also assesses the current clinical validation of the degrader platform in other malignancies, noting that these results should be interpreted as platform‑level evidence, not as oral cancer‑specific conclusions. Finally, major barriers to translation in OSCC are outlined, including inadequate disease‑specific target validation, delivery challenges, on‑target/off‑tumor toxicity and the lack of clinically relevant preclinical models. In conclusion, PROTACs offer a promising, though still nascent, therapeutic framework for OSCC, with future advancements reliant on biomarker‑guided target prioritization, oral‑cavity‑specific delivery optimization and dedicated translational research.