Drug-tolerant persister cells in head and neck squamous cell carcinoma: Molecular mechanisms and therapeutic opportunities

Although treatments for HNSCC have improved, the cancer is still challenging because many patients tend to develop the disease again nearby and often have poor recovery. Since drug-tolerant persister (DTP) cells display a wide range of types and unique genetic characteristics, nonhormonal endocrine therapies, including chemotherapy, targeted therapy and immunotherapy, are ineffective in eliminating these cells. DTP cells evade elimination by entering a reversible dormant state characterized by altered metabolism, enhanced DNA repair capacity, and modified immune escape mechanisms, all of which promote the cells’ survival and treatment failure. Platinum-based chemotherapy, widely prescribed for HNSCC, reduces tumor size but fails to confer long-term benefits because of the strong treatment resistance of DTP cells. These cells also exhibit resistance to tyrosine kinase inhibitors by activating alternative signaling pathways. Alternative survival pathways are also activated in DTP cells when targeted therapies such as those using epidermal growth factor receptor inhibitors are used. Although programmed death 1/programmed death ligand 1 inhibitors are exciting new treatments, their effect is hampered by DTP cells that affect the immune system. This review examines the ways DTP cells make HNSCC tumor cells resistant to treatment by looking at metabolic reprogramming, DNA methylation alterations and the microenvironment of the tumor. This review further explores strategies for targeting metabolic dependencies, inhibiting DNA repair, and combining therapeutic approaches, all of which can mitigate DTP cell-mediated recurrence. Advancing strategies that specifically target DTP cells could enhance HNSCC management by reducing recurrence and improving overall prognosis.