Cervical cancer (CaCx) stands as a dominant gynecological malignancy on a global scale, with an estimated annual incidence rate of 6.5% and a mortality rate of 7.7% (Globocan, 2020). Based on 2020 estimates provided by World Health Organization (WHO), CaCx stands as the fourth most prevalent cancer among women, with a staggering 604,127 new cases reported globally, accounting for 6.5% of all cancer cases. GLOBOCAN statistics reveal an alarming 341,831 deaths attributed to CaCx, representing 7.7% of all cancer-related deaths. Notably, in 2020, India bore second highest CaCx burden, with 123,907 reported cases. These figures serve as a stark reminder of need for action against this treatable malignancy, particularly through early detection and effective management strategies.

Signal Transducer and Activator of Transcription (STAT) proteins, play a crucial role in facilitating transcription directed by cytokines and growth factors (Bromberg et al., 1999). The pivotal involvement of STAT proteins extends to a diverse range of biological processes, encompassing inflammation, stemness, hematopoiesis, immune responses, and neurogenesis. Notably, among members of STAT family, STAT3 and STAT5 have garnered substantial attention for their significant associations with cancer progression (Yu et al., 2009, Igelmann et al., 2019). Among these two STAT proteins, STAT3 exhibits a robust correlation with tumor growth and immunosuppression. While STAT3 is typically activated under normal physiological conditions, its activation becomes persistent and dysregulated in context of CaCx, thereby facilitating malignant transformation. The expression of STAT3 escalates with severity of disease, highlighting its potential as a prognostic indicator for CaCx (Shukla et al., 2010). Oncogenic effects of numerous viruses often involve exploitation of JAK/STAT signaling, and human papillomavirus (HPV) is no exception to this phenomenon. HPV utilizes JAK/STAT signaling to exert its oncogenic effects and contribute to development and progression of associated malignancies (Roca Suarez et al., 2018).

HPVs are a class of small DNA viruses that play a significant role in development of various types of cancer (Harden and Munger, 2017). Globally, HPVs are responsible for approximately 5% of all human cancer cases (de Martel et al., 2017). HPVs mainly infect squamous and cutaneous epithelium containing body parts like cervix, oropharynx, head and neck squamous epithelium, anogenital epithelium and vaginal epithelium (Gheit, 2019). Persistent infection of high-risk HPV (HR-HPV) has been strongly associated with 99.7% of cervical squamous cell carcinomas, highlighting the predominant role of HR-HPV in CaCx development (Walboomers et al., 1999, zur Hausen, 2002). On the basis of their association with CaCx and precursor lesions, HPVs can be grouped into high-risk (HR) (16, 18, 31, 33, 34, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, and 70) and low-risk (LR) (6, 11, 42, 43, and 44) HPV types (Gambi et al., 2019). These HR-HPV and LR-HPV subtypes reflect oncogenic risk. Out of high-risk HPV subtypes, HPV16 and HPV18 are the most prevalent sub-types responsible for cervical carcinogenesis with a prevalence of 68.9% in Asian population. Where HPV16 accounts for 55.1% of the invasive cervical cancer cases, HPV18 accounts for only 13.8% of the cases (Ivanov et al., 2001).

The integration of HPV DNA into the host genome leads to the dysregulated overexpression of E6 and E7 oncoproteins. HPV oncoproteins E6 and E7 manipulate host cellular signaling pathways to evade immune response and promote virus persistence (Doorbar, 2005). In conjunction with E6AP ubiquitin ligase, E6 targets various proteins involved in multiple biological pathways such as PI3K, AKT, Wnt, and Notch pathways (Yang et al., 2005). E6 facilitates the ubiquitin-dependent proteasome degradation of p53, leading to the downregulation of its target genes and consequent genome instability (Chen et al., 2007). The degradation of PSD95/Dlg/ZO-1 (PDZ) proteins, including hDlg (Ginsberg et al., 2007), hScribble (Yoshida et al., 2004), MUPP1 (Lee et al., 2009), PTPN13 (Niehof et al., 2001), PATG, and MAGI, transforms the host cell (Wentzensen et al., 2004, Benekli et al., 2003). E6's degradation of NFX1-91 leads to the upregulation of hTERT, inducing cell immortalization (Ferber et al., 2003A). Additionally, the degradation of Bax, Bak (Ferber et al., 2003B), FADD (Kukimoto et al., 2006), and procaspase 8 (Thorland et al., 2000), coupled with the upregulation of cIAP-2 (Doorbar, 2006), inhibits apoptosis, consequently promoting cellular proliferation. Furthermore, the inhibition of IRF3 (Peitsaro et al., 2002), CBP/p300 (Moberg et al., 2004), ADA3 (Servidei et al., 1998), and Tyk2 (Lace et al., 2008) hampers the host's immune response to tumor cells.

Further, the integration of HPV DNA into the human genome also results in uncontrolled overexpression of the E7 oncoprotein. This overexpression inhibits transcription factors like IRF-1 (Kadaja et al., 2007) and IRF-9 (Gheit, 2019), contributing to the evasion of immune surveillance for HPV-positive tumors. E7 overexpression additionally inactivates pRb and CDK inhibitors p27 and p21, disrupting the cell cycle (Hu et al., 2021). Beyond inhibition, E7 overexpression activates the protein kinase B/Akt pathway (Pim et al., 2005) and the IL-6/Mcl-1 axis (Heinrich et al., 1998), promoting cell survival and inhibiting apoptosis, respectively.

This transcriptional regulation of HPV is linked with host cell proliferation, differentiation events, and inflammatory response (Mazibrada et al., 2008). Chronic inflammation induced oxidative DNA damage facilitates HPV integration, and subsequently, carcinogenesis (Williams et al., 2011). Therefore, targeting host transcription factors involved in inflammation and oncogenesis holds promising therapeutic potential in combating CaCx. Recent evidence suggests that STAT3 plays a crucial role in selectively promoting and sustaining a pro-carcinogenic inflammatory microenvironment during initiation and progression of cancer (Morgan and Macdonald, 2020). However, the precise molecular mechanism underlying STAT3-HPV interaction in inducing tumorigenic transformation remains unclear. Additionally, numerous studies have explored therapeutic potential of targeting STAT3 in CaCx using various cell lines, animal models, and clinical evaluations in patients. However, these studies have not been translated into clinical setup.

In this article, we have conducted a systematic examination of available data regarding interaction between STAT3 and HPV, and its potential as therapeutic target against CaCx with a special emphasis on STAT3 related pathway molecules. For this purpose, we empirically examined literature available in PubMed from initial STAT3 discovery in 1994 (Zhong et al., 1994a) till date and search was performed using following terms: STAT3 OR pSTAT3 AND Cervical cancer OR Cervical squamous cell carcinoma OR STAT3 AND Cervical Cancer AND Prognosis OR STAT3 AND Cervical cancer AND Therapeutics to highlight major deficits and practical leads in this field.