Phytochemicals and their Nanoformulations for Overcoming Drug Resistance in Head and Neck Squamous Cell Carcinoma.

Background: Drug resistance remains a significant challenge in the treatment of head and neck squamous cell carcinoma (HNSCC), leading to therapeutic failure and poor patient prognosis. Numerous mechanisms, including drug efflux pumps, altered tumor microenvironment (TME), and dysregulated cell death pathways, contribute to the development of resistance against conventional chemotherapeutic agents, immunotherapy, and targeted therapies. As resistance to traditional treatments continues to emerge, there is an urgent need for innovative therapeutic strategies to overcome these challenges. Phytochemicals are naturally occurring bioactive compounds and have demonstrated remarkable potential in targeting multiple resistance mechanisms simultaneously.

Method: This review comprehensively overviews the current understanding of drug resistance mechanisms in HNSCC and explores innovative strategies utilizing phytochemicals and their nanoformulations to overcome these resistance mechanisms, with a particular focus on recent developments and future perspectives in this field.

Results and discussion: Phytochemicals with anticancer properties include a wide range of herbal-derived molecules such as flavonoids, stilbenes, curcuminoids, alkaloids, traditional Chinese medicine, and others. These compounds can modulate ATP-binding cassette transporters, reverse epithelial-to-mesenchymal transition (EMT), target cancer stem cells (CSCs), and regulate various signaling pathways involved in drug resistance. The integration of phytochemicals into advanced nanoformulation systems has also shown a remarkable improvement in enhancing their bioavailability, stability, and targeted delivery to the TME, potentially improving their therapeutic efficacy. Furthermore, the combination of phytochemicals with conventional chemotherapeutic agents, targeted molecular therapy, and immune checkpoint inhibitors (ICIs) has exhibited synergistic effects, offering a promising approach to restoring drug sensitivity in resistant HNSCC cells.

Conclusion: Phytochemicals and their nanoformulations may improve response of HNSCC to therapy by alleviating drug resistance.