Therapeutic targeting of COX-2 in head and neck cancer: Mechanistic and clinical perspectives.

Cyclooxygenase-2 (COX-2) is a key player in inflammation; it is often over-activated in HNSCC, which consequently increases the levels of prostaglandin E2 (PGE2) (an inflammatory mediator) leading to tumor proliferation, angiogenesis, epithelial-mesenchymal transition (EMT), immune evasion, metastasis, and therapy resistance. In this review, we describe the available molecular regulation and biological function of COX-2 in HNSCC with respect to its interactions with various signaling mediators (EGFR, NF-κB, PI3K/Akt, etc.) involved in chronic inflammation. We also summarize preclinical and clinical studies examining selective COX-2 inhibitors, combinations of COX-2 inhibitors with anti-EGFR agents/chemoradiation, and potential approaches for immune modulation/ferroptosis sensitization. Although high levels of COX-2 expression have been associated with a poor prognosis and unfavorable clinicopathological characteristics; the current evidence base cannot agree on this due to the data being very heterogeneous and based largely on small or early phase studies. Pathway redundancy, biomarker differences, and potential for cardiovascular toxicity are challenges for the clinical application of targeted therapy against COX-2. In this review, we review COX-2 as a leading therapeutic target for HNSCC with an emphasis on the transition from molecular pathology to clinical application. We prioritize the discussion on (i) established clinical evidence and prognostic value, (ii) robust preclinical data supporting therapeutic combinations, and (iii) emerging strategies such as ferroptosis-sensitization and immune-modulatory approaches.