Targeted Therapies in Oral and Oropharyngeal Cancer: An Overview of Emerging and Repurposed Agents

Oral and oropharyngeal squamous cell carcinomas (OSCC and OPSCC), two major sub-types of Head and Neck cancer, remain associated with significant morbidity and exhibit poor prognosis, with limited response to conventional therapies in advanced stages. Recent therapeutic strategies have increasingly focused on molecular targets involved in tumor proliferation, angiogenesis, and immune evasion. This overview provides a concise synthesis of targeted therapies under investigation or already in clinical use, including monoclonal antibodies against epidermal growth factor receptor (EGFR) (e.g., cetuximab) and immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab), as well as inhibitors of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) or agents targeting angiogenic and intracellular signaling pathways such as VEGF and mTOR. Alongside these novel agents, growing interest surrounds the repurposing of established pharmacological agents which appear to modulate tumor-related inflammation, metabolic dysregulation, and epithelial-to-mesenchymal transition. Metformin and statins, for instance, have demonstrated anti-proliferative and pro-apoptotic effects in preclinical OSCC models. Notably, recent evidence suggests that regular use of nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, may improve survival specifically in patients with PIK3CA-altered Head and Neck tumors, potentially through modulation of the COX-2/PGE2 axis. Although prospective evidence remains limited and somewhat heterogeneous, existing preclinical and observational studies suggest that these agents may improve survival and reduce treatment-related toxicity, further pointing to the relevance of molecular stratification in guiding future repurposing strategies. This article aims to map the current therapeutic landscape, highlighting both established molecular targets and emerging repositioned drugs in the management of OSCC and OPSCC.