STAT3 and Its Targeting Inhibitors in Oral Squamous Cell Carcinoma

Oral squamous cell carcinoma (OSCC) usually originates from the precancerous lesions of oral mucosa and accounts for approximately 90% of oral cancers. Current therapeutic approaches do not yet meet the needs of patients, and the 5-year survival rate of patients with OSCC is only 50%. Recent studies have revealed that the signal transducer and activator of transcription 3 (STAT3) plays a key role in the development and progression of OSCC. STAT3 is overexpressed and constitutively activated in OSCC cells, and promotes cancer cell proliferation and anti-apoptosis, migration and invasion, angiogenesis, radiotherapy resistance, and immune escape, as well as stem cell self-renewal and differentiation by regulating the transcription of its downstream target genes. Inhibitors of the STAT3 signaling pathway have shown the promising anticancer effects in vitro and in vivo, and STAT3 is expected to be a molecular target for the treatment of OSCC. In this review, we highlight the oncogenic significance of STAT3 in OSCC with an emphasis on the therapeutic approaches and effective small molecule inhibitors targeting STAT3. Finally, we also propose the potential research directions in the expectation of developing more specific STAT3 inhibitors for OSCC treatment.


Background
Oral squamous cell carcinoma (OSCC) represents the most frequent form of head and neck squamous cell carcinoma that is the sixth most common group of cancers worldwide [1,2]. OSCC originates from the tongue, palate, floor of mouth, alveolar ridge, buccal mucosa, and other areas of oral cavity, and accounts for about 90% of oral malignancies [3,4]. In 2020, about 377,713 new patients were diagnosed with lip and oral cavity cancers, and its number of deaths was around 177,757 worldwide. Most cases were discovered in Asia [5]. The risk factors for OSCC include smoking, excessive alcohol consumption, and betel nut chewing, exposure to carcinogens, immunodeficiency, irradiation, nutrition, and genetic susceptibility, as well as viral infections including human papillomavirus and herpes simplex virus [6]. The main biologic activity of OSCC is classified as highly, moderately, or poorly differentiated along with increased aggressiveness [7]. Histologically, OSCC exhibits grades ranging from well-differentiated keratinizing carcinoma to undifferentiated nonkeratinizing carcinoma, which is more apt to spread [8,9]. Patients with OSCC are asymptomatic in the early stages, and most patients are diagnosed when OSCC further progresses, resulting in the lower survival rate [10]. Tumor infiltration, lymph node metastasis, and high rates of local recurrence are the main factors leading to death in patients with OSCC [11]. Current treatment options for OSCC include surgery, chemotherapy, radiotherapy, or a combination of therapies, depending on factors such as the extent of the disease and the patient's comorbidities [12]. However, the adverse effects of the treatment still exist. For example, salivary gland hypofunction is a common and permanent adverse effect of radiotherapy to the head and neck [13]. The common complications after selective Studies have shown that overactivation of STAT3 in many types of tumors may depend on the following mechanisms: excessive stimulation caused by overexpressed cytokines and growth factors such as interleukin-6 (IL-6), interleukin-10 (IL-10), epidermal growth factor (EGF) as well as fibroblast growth factor (FGF); hyperactivation of receptors for cytokines or growth factors; elevated activity of cytoplasmic non-receptor tyrosine kinases, such as Src and Abl kinase; loss of negative regulation for STAT3 caused by inactivation or decreased expression of endogenous negative regulators, e.g., PIAS, SOCS, and PTPs. These mechanisms can induce uncontrolled cell growth, malignant cell transformation, angiogenesis, metastasis, invasion, and immune escape [38]. Importantly, STAT3 is overexpressed and constitutively activated in OSCC, which is highly related to OSCC initiation and progression (as shown in Figure 1). For example, a recent study verified that STAT3 was a direct target of mir-125b, and circPVT1 and LncRNA MALAT1 may promote OSCC cell growth by sponging mir-125b and increasing STAT3 expression [39,40]. In addition, endogenous negative regulators such as PTPN4, SOCS5 and SOCS6 were decreased in OSCC cells, which contributed to the upregulation of p-STAT3. The upregulated p-STAT3 promoted the OSCC progression [41,42]. Emerging research demonstrates the critical role of STAT3 in OSCC [20,24,[43][44][45][46][47][48][49][50]; we herein present a comprehensive overview of its oncogenic functions in this section. Figure 1. Activation of STAT3 signaling promotes growth, metastasis, chemoresistance, immune suppression and angiogenesis in OSCC. The cytokines or growth factors bind to the corresponding receptors on the cell membrane, which further prompts STAT3 activation and subsequent regulates transcriptional activity. The whole process is divided into three steps as follows: (1) protein phosphorylation by specific kinases [20,27,28], (2) dimerization promoted by phosphorylation [52], (3) activation of gene expression by the phosphorylated dimer [53,54]. Finally, transcription and translation of the target gene regulate cell proliferation and anti-apoptosis, migration and invasion, chemoradiotherapy resistance and angiogenesis, as well as immune suppression in OSCC [23,55,56]. Reproduced/adopted in modified form from [57].

Role of STAT3 in OSCC Cell Proliferation and Anti-Apoptosis
Several studies have demonstrated that STAT3 promotes cell proliferation and inhibits apoptosis in OSCC by increasing the expression of target genes, including survivin, Mcl-1, c-Myc, Glut5, cyclin D1, B-cell lymphoma-2 (Bcl-2), and B-cell lymphoma extralarge (Bcl-xL) [23,[58][59][60]. In OSCC, STAT3 directly bound to the c-Myc promoter and promoted its transcription [61,62]; this can be blocked by silencing upstream musashi RNAbinding protein 1 (MSI1) of STAT3 signaling [63]. LncRNA P4713 promoted OSCC cell proliferation via activating the JAK/STAT3/cyclinD1 pathway. After downregulation the expression level of P471, STAT3 was found to translocate from nucleus to cytoplasm accompanied by a decrease in phosphorylation levels, which attenuated tumor cell proliferation and migration capacity [64]. Porphyromonas gingivalis and Fusobacterium nucleatum were responsible for the upregulation of cyclin D1 via IL-6/STAT3 dependent-mechanism to drive the OSCC growth [65]. MiR-769-5p restrained the Bcl-2 protein level and increased the protein levels of Bcl-2 associated X protein (Bax) and cleaved-caspase 3 by inhibiting JAK1/STAT3 activity, suggesting the important role of STAT3 in promoting the OSCC growth [66]. Furthermore, STAT3 can promote the transcription of HNF1A-AS1 in OSCC cells, HNF1A-AS1 in turn activated the Notch signaling pathway to promote OSCC cell proliferation. Conversely, depletion of HNF1A-AS1 induced apoptosis and cell cycle arrest [67]. Activation of STAT3 signaling promotes growth, metastasis, chemoresistance, immune suppression and angiogenesis in OSCC. The cytokines or growth factors bind to the corresponding receptors on the cell membrane, which further prompts STAT3 activation and subsequent regulates transcriptional activity. The whole process is divided into three steps as follows: (1) protein phosphorylation by specific kinases [19,26,27], (2) dimerization promoted by phosphorylation [51], (3) activation of gene expression by the phosphorylated dimer [52,53]. Finally, transcription and translation of the target gene regulate cell proliferation and anti-apoptosis, migration and invasion, chemoradiotherapy resistance and angiogenesis, as well as immune suppression in OSCC [22,54,55]. Reproduced/adopted in modified form from [56].

Role of STAT3 in OSCC Cell Proliferation and Anti-Apoptosis
Several studies have demonstrated that STAT3 promotes cell proliferation and inhibits apoptosis in OSCC by increasing the expression of target genes, including survivin, Mcl-1, c-Myc, Glut5, cyclin D1, B-cell lymphoma-2 (Bcl-2), and B-cell lymphoma extra -large (Bcl-xL) [22,[57][58][59]. In OSCC, STAT3 directly bound to the c-Myc promoter and promoted its transcription [60,61]; this can be blocked by silencing upstream musashi RNA-binding protein 1 (MSI1) of STAT3 signaling [62]. LncRNA P4713 promoted OSCC cell proliferation via activating the JAK/STAT3/cyclinD1 pathway. After downregulation the expression level of P471, STAT3 was found to translocate from nucleus to cytoplasm accompanied by a decrease in phosphorylation levels, which attenuated tumor cell proliferation and migration capacity [63]. Porphyromonas gingivalis and Fusobacterium nucleatum were responsible for the upregulation of cyclin D1 via IL-6/STAT3 dependent-mechanism to drive the OSCC growth [64]. MiR-769-5p restrained the Bcl-2 protein level and increased the protein levels of Bcl-2 associated X protein (Bax) and cleaved-caspase 3 by inhibiting JAK1/STAT3 activity, suggesting the important role of STAT3 in promoting the OSCC growth [65]. Furthermore, STAT3 can promote the transcription of HNF1A-AS1 in OSCC cells, HNF1A-AS1 in turn activated the Notch signaling pathway to promote OSCC cell proliferation. Conversely, depletion of HNF1A-AS1 induced apoptosis and cell cycle arrest [66].

Role of STAT3 in OSCC Cell Migration and Invasion
Epithelial-mesenchymal transition (EMT) is an important biological mechanism underlying the metastasis of primary tumors [67]. During the EMT, the characteristic of epithelial cells will convert from epithelial cells highly expressing epithelial markers (E-cadherin) to mesenchymal cells acquiring the mesenchymal markers (N-cadherin and Vimentin). This transition can promote OSCC metastasis by enhancing migration and invasion [41,68]. A recent study unveiled that the enhanced JAK2/STAT3 pathway caused the EMT of OSCC cells, and EMT could be inhibited by the JAK2 inhibitor AG490 [69]. The activated JAK2/STAT3 signaling pathway decreased E-cadherin expression and increased N-cadherin and E-box binding zinc finger protein 2 (ZEB2) expression in OSCC cells, which induced OSCC growth and metastasis [70]. Furthermore, the role of STAT3 in promoting OSCC cell migration and invasion was also linked to the upregulated expression of matrix metalloproteinase 9 (MMP-9), MMP-7, E-box binding zinc finger protein 1 (ZEB1) [66,71,72]. For example, interleukin-22 (IL-22) and IL-6 were reported to promote the migration and invasion of OSCC cells by activating the JAK/STAT3/MMP-9 signaling pathway [66,72,73]. Moreover, the cytokine-inducible Src homology 2-containing protein (CISH) and SOCS1 increased metastasis of OSCC through promoting the activation of STAT3 [74,75].

Role of STAT3 in Chemoresistance of OSCC
It has been observed that blocking STAT3 signaling enhances the anticancer activity of chemotherapies in OSCC, thus endorsing a critical role of STAT3 in regulating the chemosensitivity of OSCC [84]. Overexpression and constitutive activation of the STAT3 signaling pathway have been shown to confer chemoresistance on OSCC cells. For example, cancer stem cell-derived extracellular vesicles (CSC-EVs) promoted chemoresistance, stemness, and the metastatic potential of oral cancer cells by enhancing PI3K/mTOR/STAT3 signaling [85]. To the best of our knowledge, several recent studies have revealed the mechanisms underlying STAT3-mediated chemoresistance in OSCC cell lines. Activation of STAT3 and AKT-mediated GSK3β inactivation upregulated Mcl-1 expression, which enhanced TPF resistance in OSCC [86]. Cisplatin treatment upregulated the programmed death ligand 2 (PD-L2) and drug efflux transporter ABCG2 expression in OSCC cell lines via STAT1/3 activation [87]. Indeed, the chemoresistance of cancer cells has been reported to depend on ABC transporter activity.

Role of STAT3 in Immune Suppression
Previous work suggested that STAT3 was a powerful regulator of tumor immunosuppression, and activation of the JAK2/STAT3/PD-L1 signaling axis played a crucial role in the immune escape of osteosarcoma and cervical cancer [88,89]. In OSCC cells, STAT3 also regulated the expression of PD-L1 [90]. Protein kinase D3 (PKD3) was a key kinase mediating the activation of STAT3. Elevated PKD3 expression promoted PD-L1 expression via activating STAT3 in OSCC [91]. STAT3-mediated PD-L1 upregulation affected the proliferation and functional characteristics of T cells [92]. STAT3 was also activated in tumor-associated immune cells to induce the expression of immune suppression related genes and contribute to immunosuppression in OSCC tumor microenvironment (TME) [93,94].

Role of STAT3 in OSCC Stem Cell Phenotypes
Recently, reports have shown that the JAK2/STAT3 signaling pathway also plays a critical role in the EMT and stemness of OSCC. For example, C-C chemokine receptor 7 (CCR7) and its ligand chemokine ligand 21 (CCL21) were reported to be abnormally abundant in OSCC tissues, and CCR7 expression was correlated with EMT and the stemness of OSCC. The treatment with JAK2 inhibitor AG490 could reduce the promotive effects of CCL21 on OSCC cells colony formation and sphere formation [21]. Moreover, blocking the activation of the Jak/Stat3 pathway significantly suppressed the colony forming, invasion, migration, microsphere forming, and xenograft forming abilities of OSCC cells [95]. Overall, these results demonstrated that the JAK/STAT3 signaling pathway may contribute to the stemness of OSCC cells.

Role of STAT3 in Autophagy of OSCC Cells
STAT3 phosphorylation status is capable of influencing autophagy in OSCC cells. Compound 59, an AMPK activator, inhibited JAK/STAT3 signaling, arrested cells in the G1 phase and promoted autophagy. These findings supported the potential of compound 59 for the treatment of OSCC patients through the suppression of STAT3 pathway [96]. Icaritin significantly inhibited the level of p-STAT3 in a dose-and time-dependent manners, and further suppressed proliferation, promoted apoptosis and autophagy [97]. However, more research is needed to understand the mechanism by which STAT3 affects OSCC autophagy.

Role of STAT3 in Radiosensitivity of OSCC Cells
Recently, increasingly more studies have shown STAT3 to contribute to radioresistance. Matsuoka et al. found that the IL-6/STAT3 pathway was relevant in resistance to radiation [98], and overexpression of STAT3 reduced the radiosensitivity of OSCC cells [99]. Yu et al. showed that the expression of Pre-B-cell leukaemia homeobox 1 (PBX1) was abnormally high in OSCC, and knockdown of PBX1 substantially enhanced sensitivity to radiation in OSCC cells by inhibiting STAT3 expression [100]. These studies suggested that STAT3 was not only involved in tumorigenesis and tumor development, but also lead to radioresistance. STAT3 is emerging as a promising target for radio-sensitization of cancer radiotherapy. The mechanism underlying STAT3-mediated radioresistance was related to the suppression of apoptosis and DNA damage induced by STAT3 signaling after radiotherapy [101]. STAT3 enhanced the transcription of apoptosis regulator Mcl-1 and cell cycle regulator cyclin D2 (CCND2) to decrease the sensitivity of cancer cells to radiation, according to more research on the glioma [102], as well as colorectal cancer [103].
3.9. Role of STAT3 in Immune Cells within the OSCC TME TME is a highly complex and heterogenous ecosystem consisting of tumor infiltrating cancer cells, immune cells, and other cells. STAT3 is not only activated in cancer cells, but also becomes hyperactivated in immune cells within the OSCC TME. Some studies have suggested that activation of the JAK2/STAT signaling pathway impaired the antitumor activity of immune cells. For example, radiation treatment of head and neck cancer induced STAT3 signaling to enhance the abundance and function of regulatory T (Treg) cells and resistance to radiation therapy. STAT3 inhibition was beneficial in patients receiving radiation therapy [104]. IL-6-induced p-STAT3 increased PD-L1 and IL-10 expression in myeloid-derived suppressor cells (MDSCs), which impeded proliferation and activation of T cells and promoted Th17 cells differentiation in OSCC [94], and p-STAT3 inhibition (JSI-124) could alleviate immune suppression [42]. In addition, activation of STAT3 helped the immunosuppressive polarization of tumor-associated macrophages, which contributed to the tumor development [105]. On the contrary, overproduction of SOCS3 in dendritic cells can inhibit JAK2/STAT3 activation, as well as the differentiation and immune activity of dendritic cells, leading to their impaired antitumor effects [106]. The inconsistent role of STAT3 signaling in immune cells may be related to the difference in mechanism of action.

Targeting STAT3 for OSCC Prevention and Therapy
Abundant evidence has suggested that STAT3 may be a promising molecular target for OSCC treatment [107][108][109]. Targeting a druggable site on STAT3 or inhibiting the function of other proteins involved in the STAT3-dependent signaling cascade can directly or indirectly limit STAT3 signaling [28]. In this section, we discuss the current STAT3-targeting strategies (as shown in Figure 2) for treating and preventing OSCC, as well as the challenges in developing more specific and effective STAT3 inhibitors.
3.9. Role of STAT3 in Immune Cells within the OSCC TME TME is a highly complex and heterogenous ecosystem consisting of tumor infiltrating cancer cells, immune cells, and other cells. STAT3 is not only activated in cancer cells, but also becomes hyperactivated in immune cells within the OSCC TME. Some studies have suggested that activation of the JAK2/STAT signaling pathway impaired the antitumor activity of immune cells. For example, radiation treatment of head and neck cancer induced STAT3 signaling to enhance the abundance and function of regulatory T (Treg) cells and resistance to radiation therapy. STAT3 inhibition was beneficial in patients receiving radiation therapy [105]. IL-6-induced p-STAT3 increased PD-L1 and IL-10 expression in myeloid-derived suppressor cells (MDSCs), which impeded proliferation and activation of T cells and promoted Th17 cells differentiation in OSCC [95], and p-STAT3 inhibition (JSI-124) could alleviate immune suppression [43]. In addition, activation of STAT3 helped the immunosuppressive polarization of tumor-associated macrophages, which contributed to the tumor development [106]. On the contrary, overproduction of SOCS3 in dendritic cells can inhibit JAK2/STAT3 activation, as well as the differentiation and immune activity of dendritic cells, leading to their impaired antitumor effects [107]. The inconsistent role of STAT3 signaling in immune cells may be related to the difference in mechanism of action.

Target Upstream Regulators of STAT3
Various STAT3 inhibitors have been developed and shown some efficacy in OSCC in vitro and in vivo, which are showed in Table 1. A majority of STAT3 inhibitors have been identified to target the upstream regulators of STAT3 signaling. STAT3 is widely expressed and is transiently activated in response to EGF and IL-6. Therefore, small molecules and natural products that were able to inhibit IL-6 secretion and production, e.g., the highly pure neem leaf extract SCNE [119], magnolol [120], honokiol [107,108], and 2-O-Methylmagnolol [121], showed significant inhibitory effects on STAT3 signaling in OSCC. However, most of them also inhibited other signaling pathways in cancer cells and indicated a low level of specificity in targeting the STAT3 signaling pathway. As STAT3 is downstream to several cytokine and growth factor receptors and their associated JAKs, inhibiting JAKs by small molecular inhibitors represents a promising therapeutic option in OSCC. JAK2 inhibitors, including Licochalcone C [122] licochalcone D [123] and licochalcone H [124] were found to inhibit OSCC cell viability and induce apoptosis through tightly interacting with ATP-binding site of JAK2 and inhibiting the JAK2/STAT3 signaling pathway. In addition, all-trans retinoic acid (ATRA) showed great potential in cancer treatment through inhibition of p-STAT3 and p-JAK2 [125]. In recent years, Roxyl-ZR [126] and Alkannin [127] presented antitumor activities by hindering JAK1/STAT3 pathways in OSCC pathogenesis. Targeting the intrinsic STAT3 inhibitors, such as SOCS and PTPs, has been considered as a potential strategy for repressing STAT3 signaling pathway. For example, Bovine lactoferrin attenuated the growth of OSCC through increasing SOCS3 activation and then enhanced SOCS3-mediated STAT3 dephosphorylation and inactivation [132]. A microtubule inhibitor MPT0B098 suppressed the JAK2/STAT3 signaling pathway through modulation of SOCS3 stability in OSCC, which lead to sensitization of OSCC cells to MPT0B098 cytotoxicity [84]. Moreover, inactivated eIF5A2 induced by N1-guanyl-1,7diaminoheptane (GC7) increased cisplatin chemosensitivity in OSCC cells via inhibition of the STAT3 signaling pathway [131]. Metformin also suppressed the invasion and migration of OSCC through the inhibition of PKM2/STAT3 [136,137]. Although many small molecule agents targeting the upstream regulators exhibited potential antitumor effects through the inhibition of STAT3, other off-target pathways were also activated. Therefore, more careful and thorough pre-clinical investigations must be implemented to prevent potential harmful effects.

Directly Bind to STAT3 and Inhibit Its Activation
STAT3 inhibitors have been developed to interact with the STAT3 domains, with a major focus on the SH2 domain and the DBD. For instance, N-4-hydroxyphenylretinamide (4-HPR) was highly bound at STAT3's dimerization site and c-Abl and c-Src ATP-binding kinase sites to suppress cancer-promoting pathways including STAT3 phosphorylation, STAT3-DNA binding, and production of the trans-signaling enabling sIL-6R [138]. The STAT3 inhibitor compound (Stattic) was an SH2-domain inhibitor discovered by a highthroughput chemical library screen [109], and Stattic significantly attenuated EZH2 expression and local tumor invasion and outgrowth via targeting STAT3 [139]. However, STAT3 SH2-domain inhibitors moved slowly into clinical medicine due to high homology of the SH2 domain between STAT3 and other family members as well as high concentrations required for disruption of protein-protein interactions, which increased off-target toxicities [146].

Inhibit STAT3 Phosphorylation
Other STAT3 inhibitors were found to inhibit STAT3 phosphorylation, whereas they have not been investigated for the binding ability with STAT3 and ability to regulate upstream regulators of STAT3. For example, Niclosamide inhibited the migration and invasion in OSCC cells through the downregulation of p-STAT3 at Tyr705 [110]. Nitidine chloride acted as an apoptosis inducer in OSCC cells via inhibiting the phosphorylation of STAT3 and transcription of target genes [141,142]. Aspirin and anoctamin1 also suppressed the phosphorylation of STAT3 [140,145]. However, the mechanism of phosphorylation suppression needs to be further studied.

Nuclear-Targeted siRNA Delivery for STAT3 Gene Silencing
The STAT3 inhibitors we introduced above face many problems in their application. For example, how to target cancer cells or immune cells to improve the efficacy; the low cell permeability also prevents the inhibitors from being fully utilized; and the toxic side effects caused by off-target effects need to be addressed. Specificity and selectivity of these inhibitors of STAT3 have been questioned. Currently, a growing number of preclinical and clinical studies showed that antisense oligonucleotide (ASO)-induced STAT3 silence became a promising approach for lymphoma and lung cancer therapy. However, ASOs targeting STAT3 may cause thrombocytopenia, and toxicity limitations hindered the development of drugs [111,112]. In addition, STAT family members share a high degree of structural similarity with each other, which may induce the silence of other family members [147]. Moreover, transcription factors in different cell types usually regulate different gene networks and cellular functions, so how to target the specific cells is also crucial for the development of ideal therapeutic agents. The latest study suggested that ASO targeting STAT6 encapsulated in engineered exosome (exoASO-STAT6) was able to selectively silence STAT6 expression in macrophages [148]. This result may provide an inspiration to develop novel siRNA and antisense technology, which can specifically target STAT3 in tumor cells.

Regulate Downstream Targets of STAT3
As mentioned above, inhibitors targeting STAT3 or its upstream regulators may cause off-target effects, which are connected to the following factors: cell membranal or intracellular signals may deliver in a network, not in a single track; structural conservation of STAT family members; and diversity of STAT3 target genes. These underscore the need to develop inhibitors to regulate downstream targets of STAT3. Precise obstruction of STAT3 downstream signals could help prevent the unintended consequences of general STAT3 inhibition. For example, STAT3 has been reported to act as a transcription factor for Nicotinamide N-methyltransferase (NNMT), and upregulated NNMT in OSCC can contribute to proliferation and invasiveness [149,150]. Newly discovered NNMT inhibitors may be further proposed for OSCC treatment [113][114][115]. In addition, STAT3 was involved in the positive regulation of Sox4, Mcl-1, and so on. Genetic (siRNA) or pharmacological (Triptolide) inhibition of those targets suppressed OSCC growth in vivo [86,118]. Above all, the targeted molecules usually participate in complex signaling pathways. Although some STAT3 inhibitors have entered clinical trials in human OSCC or other malignancy (as shown in Table 2), future study should fully understand the role of STAT3 signaling in OSCC progression, which will aid in the discovery of more specific targeted therapeutics.

Conclusions
Although some progress has been made in the treatment of OSCC, its prognosis remains poor, with a 5-year survival rate of nearly 50% [10]. A comprehensive understanding of the genetic and molecular disorders of OSCC is critical for early diagnosis, appropriate treatment, and improved prognosis of patients with OSCC. The STAT3 oncogene has been reported to be overexpressed and constitutively activated in OSCC, and is associated with the poor survival outcomes [23,58]. STAT3 drives proliferation and anti-apoptosis, migration and invasion, chemoradiotherapy resistance and angiogenesis, as well as immune evasion of OSCC cells, which highlights the enormous therapeutic potential of STAT3 inhibitors.
Interestingly, contrary to its accepted tumor-promoting role, a fraction of research has shown an opposite role of STAT3 in cancer cells. It was observed that STAT3 knockdown promoted the growth of MDA-MB-231 cell-derived xenograft tumors [175]. Another finding also supported the role of STAT3 activation as a marker of favorable outcome in ER-positive/HER2-positive breast cancer patients [176]. These results imply that the oncogenic role of STAT3 in tumors might be context specific. STAT3 may be a negative regulator of certain cancer types, and therapies targeting STAT3 may therefore need to consider the origin of the tumor type.
Many STAT3-targeted therapies have been successfully developed and have shown efficacy in preclinical models of OSCC in vitro and in vivo. However, cancers including OSCC are multifaceted heterogeneous diseases [177]. OSCC has been reported to harbor multiple genetic alterations, which contribute to its initiation and progression. Therefore, STAT3 inhibition combined with other targeted therapies may be more effective for OSCC. Furthermore, many small molecule agents with potential therapeutic effects for OSCC should be further studied with a view to achieving precise drug delivery, avoiding drug side effects, and translating research findings into clinical applications. In summary, it is essential to have a comprehensive understanding of STAT3 and develop the effective approaches to inhibit the STAT3 signaling pathway with high selectivity and specificity for the treatment of OSCC.