# Recent Advances in the Targeting of Head and Neck Cancer Stem Cells
## 2 Cancer Stem Cells
### Stem Cell Factors  
Stemness, embryonic development, and tissue homeostasis are all critically regulated by SRY (Sex-Determining Region Y)-Box (SOX) transcription factors. Different members of the SOX family have been linked to the promotion of CSC characteristics in HNSCC. For example, Sox2 is frequently overexpressed and linked to aggressive behavior in HNSCC tumors [38]. The role of Sox2 in preserving HNSCC CSC pluripotency and self-renewal has also been established [39]. Because Sox2 encourages tumor initiation [40] and therapy resistance [41], it is a desirable target for therapeutic intervention [42]. Moreover, Sox9 has been connected to chemotherapy resistance and CSC characteristics in HNSCC, underlining the significance of Sox family members in these cells [43].  
An important modulator of pluripotency in embryonic stem cells is Nanog, a homeobox transcription factor. Nanog has a critical role in HNSCC in enhancing CSC features. Increased tumor growth, metastasis, and tumor-initiating capacity have all been linked to elevated Nanog expression [44]. Nanog controls genes related to stemness and proliferation, CSC pluripotency maintenance, self-renewal, and therapy resistance [45; 46].  
Furthermore, Octamer-binding transcription factors (OCTs), such as Oct3/4, Oct1, Oct6, and others, are essential for preserving stemness and controlling cellular differentiation [47; 48]. Oct3/4 is critical for HNSCC progression due to its role in tumor growth andCSC maintenance. In HNSCC, Oct3/4 expression is frequently increased, especially in CSC populations [49].  
B cell-specific Moloney murine leukemia virus Integration site 1 (Bmi-1) has also been studied extensively in relation to HNSCC. It has been discovered that HNSCC has an aberrant expression of Bmi-1, which may be related to the CSCs' proliferative behavior within the tumor. For instance, by upregulating Bmi-1, growth factors produced from endothelial cells potently support the survival and self-renewal of cancer stem cells in HNSCC [50]. Additionally, cisplatin treatment of HNSCC can induce Bmi-1 expression and augment CSC populations [51]. Twist1 and Bmi-1 work together in human HNSCC to promote EMT and stemness, suggesting an active function for Bmi-1 in HNSCC metastasis. According to [PERSON] and colleagues, these results led them to speculate that Bmi-1+ tumor cells may be CSCs in HNSCC and could be linked to therapeutic resistance in vivo [52; 53].  
The transcription factor Klf4 (Kruppel-like factor 4) has recently drawn interest in relation to HNSCC [54]. Klf4 has been shown in several studies to function as a tumor suppressor [55], preventing the growth of cancer cells and promoting differentiation, but it has also been reported that Klf4 acts as an oncogene [56]. The recent study by [PERSON] and colleagues corroborates the oncogenic role of Klf4 in HNSCC, demonstrating that Klf4 binds to super-enhancers and directs the transcriptional upregulation of cancer genes promoting cancer progression and global transcriptional changes [54]. Moreover, a worse disease-specific survival was connected with the persistence of Klf4 expression [57]. However, studies analyzing Klf4 expression in HNSCC cases compared to normal tissue showed both decreased and elevated Klf4 expression [57; 58].