The TEAD (TEAD1-4) transcription factor family acts as the key terminal regulatory factor in the Hippo signaling pathway. They regulate cellular development, proliferation, and tissue homeostasis by modifying target genes. A recent study has demonstrated a strong correlation between the abnormal expression and activation of TEAD and the development and clinicopathological features of human malignant tumors, including oral squamous cell carcinoma (OSCC) (1–3). The expression of abnormal TEAD has been observed to impact important oncogenes, including MYC (4, 5), KRAS (6), BRAF (7), LKB1 (8), and NF2 (9, 10). The transcriptional activity of TEAD is crucial in multiple facets of tumor formation, encompassing tumor advancement, spread to other parts of the body, metabolic changes, immunological responses, and drug resistance mechanisms. Previous TEAD-related studies have predominantly concentrated on the examination of TEAD activity through the analysis of Hippo pathway kinases and YAP/TAZ proteins. However, recent findings have brought attention to the significance of post-translational alterations, intercommunication between carcinogenic signaling pathways, and nuclear localization dynamics as pivotal factors influencing TEAD activity. TEAD interacts with various transcription factors associated with signal transduction pathways, such as transcription factor (TCF) (11), activating protein 1 (AP-1) (12), MRTF (13), SMADs (14), and OCT4 (15), in addition to YAP/TAZ in the Hippo pathway. Recent research has found evidence that the disruption of the hippocampal signaling pathway is associated with various types of cancer, such as oral cancer, breast cancer, colorectal cancer, and cholangiocarcinoma (2, 16). A significant amount of research has been dedicated to studying therapeutic methods that focus on specifically targeting and locating the phosphorylation of YAP/TAZ within subcellular structures. Nevertheless, the inherent conformation of the YAP/TAZ protein structure is naturally unfolded, providing difficulties for potential drug development. Consequently, the TEAD protein presents itself as a potentially effective target for manipulating the Hippo pathway (17). In this review, a comprehensive analysis of recent progress in targeted therapy for OSCC was discussed with a particular focus on the transcriptional mechanism and involvement of TEAD in oncogenic signaling. Consequently, this study provides innovative viewpoints and a theoretical basis for future drug development and clinical implementation targeting TEAD.

OSCC is the most prevalent form of head and neck squamous cell carcinoma (HNSCC). It typically occurs in the lips, gums, tongue, oral cavity, and palate. OSCC significantly impacts human health and overall well-being, with a 5-year survival rate of around 50% (18, 19). The main clinical strategy for OSCC is a combination of surgery, radiation, and chemotherapy, which are determined based on the tumor’s stage and pathological diagnosis. Cisplatin (CDDP), paclitaxel, 5-fluorouracil, and doxorubicin are potential clinical medicines for OSCC in the form of monotherapy or combination (20). Nevertheless, some constraints, such as restricted therapeutic effectiveness, systemic toxicity, and drug resistance, have raised more and more attention during these conventional therapies (21).

The utilization of nanotechnology has facilitated the implementation of intelligent drug delivery systems (DDS) for targeted therapy in OSCC (22–24). Nanoparticles with particular physical and chemical characteristics, significantly improve therapeutic efficacy by providing precise administration of drugs and minimizing systemic drug exposure during oral cancer therapy (25, 26). These nanoparticles could be prepared by many forms of materials, including lipids, polymers, metals, and metal oxides (27–31). The unique characteristics of the microenvironment, including decreased pH levels, elevated concentrations of reactive oxygen species, and the excessive expression of certain enzymes and receptors, offer an alternative strategy for targeted therapy against OSCC (32). Therefore, there has been an application of a novel generation of tumor-responsive DDSs in the recent therapy of OSCC (33). Furthermore, as evidenced by the observed disparities between the tumor environment and normal tissues, stimulus-responsive DDS have demonstrated great potential in preclinical investigations (34), but are still hindered by the inherent instability and lack of control in the tumor microenvironment. Hence, the improvement of sensitivity and controllability of stimulus-responsive DDS is necessary to obtain more satisfactory clinical effects.

Active targeted therapy, which is different from passive targeted therapy, primarily targets specific receptors located on the surface of tumor cells, dramatically enhancing medication specificity by specifically supplying ligands on nanocarriers (35). Active targeted therapy has exhibited satisfactory feasibility for OSCC therapy, including gene therapy, immunotherapy, and biomimetic technologies (36). The utilization of gene therapy has attracted significant interest in the field of cancer for the treatment of hereditary and monogenic disorders (37). Gene therapy shows great potential in preventing the recurrence of OSCC by providing specific targets towards malignant regions (38). Most importantly, compared to traditional therapeutic modalities, gene therapy offers an accurate molecular-level OSCC treatment. However, before the application of gene therapy in clinical therapy, the exploration of suitable vectors is crucial for the effectiveness of transfection and successful introduction of the target gene.

Immunotherapy is a new strategy for treating OSCC that involves either blocking the immune system’s ability to detect cancer cells or boosting the immune response at the tumor site (39–42). Immunotherapy for oral cancer focuses on many immunological mechanisms and important checkpoints, including programmed death-1, and PD-L1 (36). However, the noticeable therapeutic advantages of OSCC have only been witnessed in a restricted subset of patients due to the diverse characteristics of patients, such as smoking and alcohol intake.

Much research has been dedicated to investigating changes in gene or protein expression within neoplastic cells through the identification of atypical genetic and epigenetic mutations. Previous research has shown that using specific molecular markers and receptors has great potential as a therapeutic strategy to selectively increase the expression of genes and direct targeted drug delivery to cancerous tissues (43). In recent times, the search for new biomarkers that may improve OSCC diagnosis, therapy, and prognosis has attracted a lot of attention. These biomarkers also hold promise for reducing negative effects and advancing precision medicine. Unfortunately, the available choices for treating patients with advanced oral cancer are still restricted, which puts forward the requirement for the exploration of novel therapeutic targets for OSCC.

Transcription enhancer factors (TEFs), commonly referred to as TEAD transcription factors, were initially identified in 1987 (44). The nucleoproteins were first identified as positive trans-enhancer factors because of their capacity to bind to the overlap element of the SV40 enhancer B1 region. Later, it was shown that TEAD may bind to the human papillomavirus-16 (HPV-16) enhancer and activate the HPV-16 oncogenes E6/E7 (45). TEAD, as a highly conserved transcription factor, could be observed for its similarity in most eukaryotes (46). Mammalian species possess four TEAD genes: TEAD1 (also known as TEF-1/NTEF), TEAD2 (also known as TEF-4/ETF), TEAD3 (also known as TEF-5/ETFR-1), and TEAD4 (also known as TEF-3/ETFR-2/FR-19).

A notable similarity of the domain architecture could be observed in TEAD proteins, as depicted in Figure 1 . The N-terminal TEA/ATTS domain of the TEAD protein folds similarly to other TEAD domains in order to interact with DNA. Additionally, a C-terminal deactivation domain that facilitates the recruitment of coactivators for binding to transcription target genes could also be observed (47). Notably, the level of similarity across human TEAD components in the DNA binding domain (DBD) exceeds 99%, endowing DBD to be the most conserved region within TEAD proteins (48). 5’-CATTCCA/T-3’, a highly conservative DNA binding site in the TEAD family, is commonly referred to as the MCAT element (49, 50). The C-terminal region, which contains the YAP binding domain (YBD), has been verified to be conserved (51). Linking to DNA is indicated by the location of the majority of TEADs within chromatin (52), but only minimal transcriptional activity could be provided by TEADs (53).

TEAD1, TEAD3, and TEAD4 display significant expression in multiple tissues, including pancreas, lung, heart, placenta, and others. In contrast, TEAD2 is selectively present in embryonic tissues such as the limbs, cerebellum, and testis but is largely absent in adult tissues (54). Although there is a significant similarity of human TEAD1-4, each TEAD protein has distinct expression in specific tissues, indicating the distinct function of each TEAD. Studies on gene inactivation have provided insights into the physiological roles of TEAD genes in mice. TEAD1 contributes significantly to the formation of the developing heart and enhances the expression of cardiac genes. Deletion mutations in TEAD1 result in embryonic death and defects in cardiac development (55). Nevertheless, there are divergent findings and controversies concerning the role of TEAD2. Kaneko et al. have documented that the deactivation of the TEAD2 gene substantially heightens the susceptibility to neural tube closure abnormalities in mice, commonly referred to as anencephaly (56). However, Sawada et al. reported that embryos with TEAD2 deletion were normal (57). The research conducted by Sawada et al. presented proof of the mutual participation of TEAD1 and TEAD2, as the mice with mutations in both TEAD1 and TEAD2 showed more prevalent malformations. TEAD3 has been demonstrated to exhibit specific expression in the placenta and various embryonic tissues (58, 59). Bone marrow genes and the development of trophectoderm are both regulated by TEAD4 (60, 61). Consequently, the inhibition of TEAD4 leads to the inability of the embryo to successfully implant into the endometrium (62). Additional research is necessary to examine the extent to which unique TEAD homologs complement one another in diverse physiological and carcinogenic contexts, as well as how their synergistic potential varies across different tissue types.

The main regulatory mechanism of TEAD transcriptional activity is mainly related to binding coactivators. Notable transcriptional coactivators that impact TEAD function include Yes-associated protein (YAP), transcription coactivator with PDZ-binding motif (TAZ, also referred to as WWTR1), VgLL protein, and p160 protein (63).

YAP and TAZ (YAP/TAZ) are the targets and end-effectors of TEAD in the hippo pathway. They are found in the cytoplasm and are unable to bind to TEAD when LATS1/2, which is a large tumor suppressor kinase, is phosphorylated. This inhibits the activation of TEAD transcription. After being dephosphorylated, the YAP/TAZ complex is transported to the nucleus where it interacts with TEAD to promote the transcription of target genes that are essential for cellular growth, survival, and division. The inactivation of LATS1/2, dephosphorylation, and consequent aggregation of YAP/TAZ inside the nucleus are further caused by the down-regulation of the Hippo pathway. These aggregates then bind to TEAD and up-regulate the expression of specific genes, such as connective tissue growth factor (CTGF) and Cyr61 (64, 65). In conclusion, inhibition of the hippo pathway could achieve multiple biological behaviors, including the promotion of the movement of YAP/TAZ to the nucleus, binding with the TEAD transcription factor in the transcription enhancer-associated domain, stimulating the expression of target genes, and enhancing cell proliferation (66).

Furthermore, there are TEAD coactivators that are not associated with the hippo route. The Vestigial-like (VGLL) protein family includes four coactivators: VGLL1, VGLL2, VGLL3, and VGLL4. The regulation mechanism of VGLL on TEAD has been demonstrated to be related to gene expression. Because the binding sites on TEAD that the VGLL family proteins have overlap with the binding sites of YAP/TAZ, they compete with YAP/TAZ for TEAD binding, which inhibits the development of tumors (67). TEAD4 interacts directly with TCF4 through its TEA domain, contributing to the deactivation of TCF4 and the regulation of Wnt target genes (11). Previous studies have shown a clear and direct connection between AP-1 and TEAD. AP-1 is crucial for activating target genes that are important for the development and progression of tumors (12). Additionally, the interaction between steroid receptor coactivators belonging to the p160 family and TEAD has been confirmed (68). Other coactivators, including poly (adp-ribose) polymerase (69), serum response factor (70), myocyte enhancer factor 2 (71), and myc-associated factor X, have been found to be related to TEAD transcription (72). Nevertheless, recent studies have shown that the transcription activity of TEAD may be regulated by post-translational modifications and changes in its location within the cell.

S-palmitoylation is a type of post-translational modification that affects the activity of the TEAD family. This modification occurs independently of the binding of coactivators. The palmitoylation sites in TEAD have been identified as three conserved cysteine residues. Palmitoylation in TEAD is essential for controlling protein stability (73) and transcriptional activity (74). The S-palmitoylation of TEAD1 plays a crucial role in the binding and regulation of YAP/TAZ, and has significant biological significance. The structural changes in TEAD2 palmitoylation resulted in a significant decrease in the abundance of TEAD2 protein, primarily due to the reduction in protein stability (73). Palmitoylation is of specific significance in both protein transport and membrane localization (75), while TEAD palmitoylation does not impact its localization or binding to the membrane (73, 74). The results of structural investigations indicate that TEAD’s palmitoyl group is located inside a deep hydrophobic cavity. However, it is yet unknown if TEAD depalmitoylation mechanism can be controlled and if TEAD palmitoylation is a dynamic process.

Different from post-translational changes, transcription factors can be spatially regulated to modify transcriptional activity. Although studies on subcellular changes in TEAD localization are limited, the regulation mechanism of nuclear translocation of TEAD in target gene expression obtains more and more evidence. Recently, the influence of environmental stresses in TEAD subcellular localization has been demonstrated. The cytoplasmic localization of TEAD and its transcriptional inactivation are significantly increased by hypertonic stress, high cell density, and cell detachment, as reported in a study (76). The process of hypertonic stress-induced TEAD cytoplasmic localization is proven to be facilitated by p38, rather than the Hippo pathway. During extended osmotic stress, p38 binds directly to TEAD and moves TEAD to the cytoplasm, which leads to the suppression of TEAD transcription (77). Nevertheless, the specific biochemical process by which cell density triggers TEAD cytoplasmic localization has yet to be fully understood.

The subcellular location of TEAD has been demonstrated to exert a dominant influence on the regulatory signaling pathway of YAP/TAZ, hence impeding the growth of cancer cells driven by YAP (78). The translocation of YAP/TAZ into the cytoplasm under osmotic pressure is attributed to the translocation of TEAD. Furthermore, alterations in the subcellular location of TEAD can also contribute to the control of TEAD gene expression and determining the output of Hippo signaling.

TEAD has been observed to be overexpressed in OSCC and other types of cancer. The involvement of TEAD in the process of carcinogenesis and the therapeutic advantages of TEAD targeting have gotten much attention based on experimental findings and emerging data. Although significant advancements in comprehending the hippocampus route, there are still unsolved inquiries in OSCC. Further in vivo validation is necessary in order to substantiate our existing in vitro findings. The investigation of TEAD expression in OSCC and its oncogenic mechanism is currently underway.

There are two crucial matters that require attention in the upcoming research. The initial aspect pertains to the intricate sequence of TEADs implicated in the advancement of tumors, encompassing tumor formation, EMT, resistance to drugs, metastasis, and many molecular mechanisms and activities. Despite an increasing understanding of the carcinogenic role of the TEAD transcription factor, the specific mutation responsible for driving carcinogenesis remains unclear. The expression and activation of TEADs may be determined by abnormal DNA copy number, transcriptional regulation, post-transcriptional regulation of miRNA, and post-translational modification of subcellular localization. A comprehensive analysis and examination of TEAD transcription co-activators will provide a clearer understanding of the dual function of TEADs in both normal and abnormal physiological processes. Furthermore, there remains a need for further development and research on medications targeting TEADs. Although various small-molecule TEAD inhibitors have demonstrated promise anti-tumor effects in preclinical research and are in clinical trials, inhibitors with high selectivity and low nephrotoxicity remain to be discovered. Given that TEAD plays a significant part in important pathways related to tumor progression, further progress in comprehending the regulatory mechanisms of TEAD and creating therapeutic interventions will create a stimulating new area for fundamental scientific research and pharmaceutical development.