Oral Cancer Stem Cells: A Comprehensive Review of Key Drivers of Treatment Resistance and Tumor Recurrence

Oral squamous cell carcinoma (OSCC) remains a major cause of morbidity and mortality worldwide with high recurrence rates and resistance to conventional therapies. Recent studies have highlighted the pivotal role of oral cancer stem cells (OCSCs) in driving treatment resistance and tumor recurrence. OCSCs possess unique properties, including self-renewal, differentiation potential, and resistance to chemotherapy and radiotherapy, which contribute to their ability to survive treatment and initiate tumor relapse. Several signaling pathways, such as Wnt/β-catenin, Hedgehog, Notch, and PI3K/Akt/mTOR, have been implicated in maintaining OCSC properties, promoting survival, and conferring resistance. Additionally, mechanisms such as drug efflux, enhanced DNA repair, epithelial-mesenchymal transition (EMT), and resistance to apoptosis further contribute to resilience. Targeting these pathways offers promising therapeutic strategies for eliminating OCSCs and improving treatment outcomes. Approaches such as immunotherapy, nanotechnology-based drug delivery, and targeting of the tumor microenvironment are emerging as potential solutions to overcome OCSC-mediated resistance. However, further research is needed to fully understand the molecular mechanisms governing OCSCs and develop effective therapies to prevent tumor recurrence. This review discusses the role of OCSCs in treatment resistance and recurrence and highlights the current and future directions for targeting these cells in OSCC.