Quercetin in oral squamous cell carcinoma: Integrating immunometabolic reprogramming, cancer stem cell plasticity, and precision therapeutic strategies.

Oral squamous cell carcinoma (OSCC) remains a major clinical challenge because of its recurrence, metastasis, and therapeutic resistance. Quercetin, a dietary flavonoid, has shown broad anticancer activity in experimental models of OSCC through the modulation of several processes, including apoptosis, autophagy, oxidative stress, epithelial-mesenchymal transition (EMT), cancer stem cell (CSC) phenotypes, metabolism, inflammation, and oncogenic signalling. However, the available evidence remains largely preclinical, and no clinical trial has demonstrated an improvement in progression-free survival or overall survival with quercetin in OSCC. Limited tumour exposure, poor predictability of pharmacokinetic behaviour, and the absence of validated predictive biomarkers further restrict its clinical translation. This review therefore moves beyond a pathway-based description of quercetin activity and discusses its potential within a biomarker-guided and translational framework. The roles of patient-derived organoids (PDOs), molecular profiling, and multi-omics approaches in identifying OSCC subgroups that may be sensitive to quercetin and in understanding response and resistance mechanisms are explored. In addition, artificial intelligence (AI)-assisted approaches are considered for the rational prioritization of combination therapies, integration of molecular and pharmacological data, and optimization of patient selection. We propose a stepwise development strategy involving PDO-guided studies, pharmacokinetic optimization, biomarker-enriched early-phase trials, and subsequent evaluation of clinically meaningful outcomes in randomized studies. These approaches may help define the patient populations and treatment settings in which quercetin could have therapeutic value in OSCC.