It has now become increasingly clear that viruses, which may not be directly oncogenic, can affect the biology of tumors as well as immune behavior against tumors. This has led to a fundamental question: Should tumors associated with viral infection be considered distinct from those without? Typically, viruses activate the host innate immune responses by stimulating pathogen recognition receptors and DNA-sensing pathways, including the stimulator of interferon genes (STING) pathway. However, regulation of the STING pathway in a virus-associated tumor microenvironment is poorly understood. Human papillomavirus (HPV) infection within a subset of head and neck squamous cell carcinomas (HNSCC) promotes a unique etiology and clinical outcome. For reasons currently not well understood, patients with HPV+ tumors have a better outcome in terms of both overall survival and reduced risk of recurrence compared with HPV HNSCC. This observation may reflect a greater intrinsic immunogenicity associated with HPV infection, pertaining to innate immune system pathways activated following recognition of viral nucleotides. Here we discuss how HNSCC provides a unique model to study the STING pathway in the context of viral-induced tumor type as well as recent advances in our understanding of this pathway in HSNCC.

The concept of viral etiology in cancer has been long appreciated, with research over the past 30 years providing a thorough understanding of the causal role viruses can play in malignancy. Seven viruses—Epstein–Barr virus (EBV), hepatitis B virus (HBV), human T-lymphotropic virus type 1 (HTLV-1), human papilloma virus (HPV), hepatitis C virus (HCV), Kaposi sarcoma herpesvirus (KSHV), and Merkel cell polyomavirus (MCV)—have thus far been directly implicated in the development of around 12% of cancers (Table 1; refs. 1–9). Other viruses, such as human cytomegalovirus (HCMV), have also been proposed as human oncoviruses but their causal effect on cancer development remains controversial (10). The established oncoviruses are derived from heterogenous viral families, generally display ubiquitous infection within populations, and can be direct (EBV, HTLV-1, HPV, KSHV, and MCV) or indirect (HBV and HCV) carcinogens via the use of diverse tumorigenic mechanisms (11). Direct transformations are caused by the expression of viral oncogenes that drive genetic alterations and tumor initiation or at later stages, modulate tumor cell signaling pathways to promote tumor growth (12).

Table 1.

Properties of human oncoviruses within their respective cancers.

VirusAssociated cancersPathologic impact of virus
EBV (3) Burkitt lymphoma Lymphomas derived from EBV-driven translocation of c-MYC gene and an immunoglobulin locus in B cells that promotes proliferation and immortalization. 
 Immunoblastic lymphomas  
 Hodgkin lymphoma  
 NK-cell and T-cell lymphomas  
 Diffuse large B-cell lymphoma Latent EBV infection drives clonal expansion of epithelial cells that can develop into carcinomas. 
 Primary effusion lymphoma  
 Leiomyosarcoma  
 Nasopharyngeal carcinoma Inflammatory precursory lesions and lymphocytic infiltration common in all EBV-driven cancers. Each EBV-driven tumor expresses unique combination of EBV latent gene products that produce different genetic and epigenetic modifications. 
 Gastric carcinoma  
HBV (4) Hepatocellular carcinoma Chronic HBV infection of the liver promotes long-term inflammation and upregulated hepatocyte proliferation. HBV is associated with increased risk of developing cancer following or alongside other etiologic factors, such as chronic hepatitis and cirrhosis. 
HTLV-1 (5) Adult T-cell lymphoma (ATL) Viral products create immunosuppressive environment that allows HTLV-1–infected T cells to rapidly proliferate and transform. 
HPV (6) Squamous cell carcinomas of the cervix, vulva, vagina, penis, anus, and oropharynx High-risk subtype (particularly HPV16 and HPV18) expression of the major oncogenes E6 and E7 degrade p53 and pRB, respectively, to promote cell proliferation. 
HCV (7) Hepatocellular carcinoma Chronic HCV infection of the liver promotes long-term inflammation and oxidative stress. HCV viral proteins can also inhibit pRB and p53 tumor suppressor genes to upregulate proliferation and division. Requires additional risk factors, such as liver disease, diabetes mellitus, and obesity for cancer development. 
KSHV (8) Kaposi sarcoma KSHV infection of endothelial cells or circulating endothelial progenitors alters cell metabolism, gene expression, and growth rate that aid in the promotion of proangiogenetic properties. Further risk factors are required for tumor development, such as HIV infection or other means of immunosuppression. 
 Primary effusion lymphoma KSHV latent infection of B cells promotes oncogenesis via repression of p53 and pRB, constitutive activation of NFκB, and IL6-induced VEGF production. 
MCV (9) Merkel cell carcinoma (MCC) MCV clonally integrates into MCC tumor genome, and persistent expression of MCV T antigens promotes tumor cell proliferation and survival. 
VirusAssociated cancersPathologic impact of virus
EBV (3) Burkitt lymphoma Lymphomas derived from EBV-driven translocation of c-MYC gene and an immunoglobulin locus in B cells that promotes proliferation and immortalization. 
 Immunoblastic lymphomas  
 Hodgkin lymphoma  
 NK-cell and T-cell lymphomas  
 Diffuse large B-cell lymphoma Latent EBV infection drives clonal expansion of epithelial cells that can develop into carcinomas. 
 Primary effusion lymphoma  
 Leiomyosarcoma  
 Nasopharyngeal carcinoma Inflammatory precursory lesions and lymphocytic infiltration common in all EBV-driven cancers. Each EBV-driven tumor expresses unique combination of EBV latent gene products that produce different genetic and epigenetic modifications. 
 Gastric carcinoma  
HBV (4) Hepatocellular carcinoma Chronic HBV infection of the liver promotes long-term inflammation and upregulated hepatocyte proliferation. HBV is associated with increased risk of developing cancer following or alongside other etiologic factors, such as chronic hepatitis and cirrhosis. 
HTLV-1 (5) Adult T-cell lymphoma (ATL) Viral products create immunosuppressive environment that allows HTLV-1–infected T cells to rapidly proliferate and transform. 
HPV (6) Squamous cell carcinomas of the cervix, vulva, vagina, penis, anus, and oropharynx High-risk subtype (particularly HPV16 and HPV18) expression of the major oncogenes E6 and E7 degrade p53 and pRB, respectively, to promote cell proliferation. 
HCV (7) Hepatocellular carcinoma Chronic HCV infection of the liver promotes long-term inflammation and oxidative stress. HCV viral proteins can also inhibit pRB and p53 tumor suppressor genes to upregulate proliferation and division. Requires additional risk factors, such as liver disease, diabetes mellitus, and obesity for cancer development. 
KSHV (8) Kaposi sarcoma KSHV infection of endothelial cells or circulating endothelial progenitors alters cell metabolism, gene expression, and growth rate that aid in the promotion of proangiogenetic properties. Further risk factors are required for tumor development, such as HIV infection or other means of immunosuppression. 
 Primary effusion lymphoma KSHV latent infection of B cells promotes oncogenesis via repression of p53 and pRB, constitutive activation of NFκB, and IL6-induced VEGF production. 
MCV (9) Merkel cell carcinoma (MCC) MCV clonally integrates into MCC tumor genome, and persistent expression of MCV T antigens promotes tumor cell proliferation and survival. 

The majority of oncoviruses exhibit latent infection that can, over time, contribute to the development of cancer (11). They are generally unable to activate tumorigenesis alone and require the involvement of other factors such as host mutations, immunosuppression, or chronic inflammation (13). For example, persistent HBV and HCV infections aid in the development of chronic liver inflammation, which in turn is required for the induction of viral-initiated hepatocellular carcinoma (4). EBV, KSHV, and HTLV-1 have recently been found to induce chronic inflammation, mediated by persistent activation of STAT3 and NFκB, that creates a favorable environment for latent infection and subsequent cancer development (14). Viral infections are largely controlled by the induction of type-I IFNs that upregulate effector immune functions to generate potent antiviral activity (15). In the context of both chronic viral infections and cancer, type-I IFN overexpression has been found to create a coexisting inflammatory and immunosuppressive environment that can promote pathogen survival or tumor persistence (15, 16). The tumor microenvironment is a complex system within all cancer phenotypes, but the unique interplay of oncoviruses and the immune system within viral-associated cancers creates further intricacy that remains to be fully elucidated. In this review, we will focus on HPV-enriched tumor microenvironment in head and neck cancers (HNC), as little is understood about the innate immune sensing mechanisms involved in the pathogenesis of this disease.

HPV is a sexually transmitted circular double-stranded DNA virus with over 200 identified subtypes that are categorized as either high or low risk (17). The majority of infected individuals clear HPV within 12 to 24 months, but high-risk types, particularly HPV16 and HPV18, can persist as latent infections increasing the risk of developing cancer. High-risk HPV can integrate into host DNA and inactivate tumor suppressor proteins, primarily through the action of the E6 and E7 oncogenes on p53 and the retinoblastoma protein (pRB), respectively (18). Infection with high-risk HPV was first recognized to have a causal role in cervical cancer in the early 1980s and HPV is now understood to be implicated in 99.7% of all cervical squamous cell carcinomas (SCC; ref. 19). Over the years, high-risk HPV has been classified as a carcinogen in many other SCC, including oropharyngeal cancer, a type of HNC that develops in the oropharynx (tonsil and base of tongue; ref. 20).

HNCs, of which the majority are head and neck squamous cell carcinoma (HNSCC), represent a heterogeneous cluster of aggressive malignancies (21). The incidence of HNC has increased by approximately 30% since 1990 (21) and it is now the seventh most common cancer worldwide (22). Prognosis greatly varies depending on the anatomic origin and stage of disease, with overall 5-year survival approximately 60% (23). One third of patients with HNSCC are diagnosed with early-stage disease (stage I or II) that can be successfully cured with either surgery or radiotherapy, depending on the accessibility of the tumor (24). The majority of patients present with locally advanced disease (stage III or IV), which includes large primary tumors and/or metastatic spread to cervical lymph nodes. Locally advanced disease is associated with poor prognostic outcomes due to the high likelihood of locoregional recurrence and/or distant metastatic spread (25). Standard of care is typically multi-modal, comprising ablative surgery followed by risk-stratified adjuvant radiotherapy ± chemotherapy or primary concurrent chemoradiotherapy (26).

Increasing numbers of oropharynx SCC (OPSCC) are now associated with HPV infection (27). Underlying oral infection with predominantly HPV16 produces an etiologically distinct HPV+ OPSCC phenotype that could be attributed to p53 inactivation by the E6 oncogene and the simultaneous upregulation of the tumor suppressor gene P16 by E7 (28). This generates an opposing phenotype to HPV HNSCC, which commonly have mutated p53 (29) and lack expression of P16 (30). The incidence of HPV+ and HPV HNSCCs have also been trending in opposite directions, with HPV-associated OPSCCs significantly increasing in numbers over the past 30 years (31, 32). Along with true increases of HPV+ HNSCC cases, improved understanding of the causal role of HPV and enhanced diagnostic methods have led to increased prevalence of this disease in the population (33).

The significant impact HPV has on the HNSCC phenotype and surrounding immune environment opens an important question: should HPV+ and HPV HNSCCs be regarded as distinct entities? For reasons currently not well understood, patients with HPV+ tumors have a better outcome in terms of both survival and reduced risk of recurrence compared with HPV HNSCC (34). It is reasonable to postulate that this observation reflects a greater intrinsic immunogenicity associated with HPV infection, pertaining to innate immune system pathways, activated following recognition of viral nucleotide compounds. One such pathway is the stimulator of interferon genes (STING), a recently described pathway that forms a central component of our response to infection-sensing parasitic, bacterial, or viral DNA in the cytosol and inducing type-I IFNs (IFNα and IFNβ) in response (35).

STING is an endoplasmic reticulum (ER)–associated adaptor protein encoded by the transmembrane protein 173 (TMEM173) gene (36). Cyclic GMP-AMP synthase (cGAS) directly binds double-stranded DNA in the cytosol and catalyzes the production of the cyclic dinucleotide (CDN) 2′3′-cGAMP from a molecule of AMP and GMP (37). STING can be activated by these CDN compounds and also directly by cytosolic DNA (35). Activated STING undergoes a conformational change that allows the protein to traffic to the Golgi via the ER–Golgi intermediate compartment. At perinuclear regions, TANK-binding kinase 1 (TBK1) can be recruited and activated by STING, leading to the recruitment and phosphorylation of IFN regulatory transcription factor 3 (IRF3; ref. 38). Dimerization of phosphorylated IRF3 allows its translocation into the nucleus and initiation of type-I IFN gene transcription (Fig. 1). Recent studies suggest that STING-dependent stimulation of type-I IFNs is essential for antitumor immune responses, as defective intratumoral priming of CD8+ T cells is observed in mice lacking STING (39, 40).

Figure 1.

The STING pathway and possible effects of HPV on STING signaling. Cytosolic double-stranded DNA (dsDNA) can originate from pathogenic or self-DNA sources. The DNA sensor cGAS detects cytoplasmic dsDNA and activates STING, inducing a conformational change that allows its translocation from the ER to Golgi. At perinuclear regions, STING activates TBK1 and NFκB. Activated TBK1 leads to IRF3 phosphorylation and production of type-I IFNs and proinflammatory cytokines. Within the tumor microenvironment, increased STING-dependent IFNs can prime tumor-specific CD8+ T cells and allow dendritic cell (DC) maturation. Involvement of HPV16 E7 in HNSCC cell lines has demonstrated the ability to inhibit STING at the protein level. E7 interactions via its LXCXE motif can directly inhibit STING and subsequent downstream signaling through mechanisms not fully understood. E7 can also interact with the mitochondrial-localized immune system regulator NLRX1 to destabilize and facilitate the autophagic degradation on STING.

Figure 1.

The STING pathway and possible effects of HPV on STING signaling. Cytosolic double-stranded DNA (dsDNA) can originate from pathogenic or self-DNA sources. The DNA sensor cGAS detects cytoplasmic dsDNA and activates STING, inducing a conformational change that allows its translocation from the ER to Golgi. At perinuclear regions, STING activates TBK1 and NFκB. Activated TBK1 leads to IRF3 phosphorylation and production of type-I IFNs and proinflammatory cytokines. Within the tumor microenvironment, increased STING-dependent IFNs can prime tumor-specific CD8+ T cells and allow dendritic cell (DC) maturation. Involvement of HPV16 E7 in HNSCC cell lines has demonstrated the ability to inhibit STING at the protein level. E7 interactions via its LXCXE motif can directly inhibit STING and subsequent downstream signaling through mechanisms not fully understood. E7 can also interact with the mitochondrial-localized immune system regulator NLRX1 to destabilize and facilitate the autophagic degradation on STING.

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STING expression has previously been characterized within the different tissues of the tongue (41). High levels of STING were found in the submucosal endothelial cells and immune cells. In the oral mucosa STING expression was detected in the basal cells that was then lost after keratinocyte differentiation (41). The unique presence of transitional mucosa in the oropharynx may also explain the preference for oropharyngeal HPV infection (42), indicating there may be a unique association between the DNA virus infection route and associated detection pathway in HPV+ HNSCC.

Upregulated STING expression in HPV+ HNSCC was first described by Baird and colleagues in 2017 (41). STING was detected in the local immune cells of both HPV phenotypes, but expression was significantly higher within the HPV+ HNSCC tumor cells themselves. HPV HNSCC generally originates in the keratinizing layers of the epithelium (43), providing a potential explanation for the diminished STING found in these tumor cells following keratinocyte differentiation. Intratumoral injection of STING-activating CDNs in the murine papilloma and HNSCC models resulted in rapid regression of papilloma, showing better results than the widely used immunomodulatory therapy with a TLR-7 agonist, imiquimod. The effects of combining STING agonist with established cetuximab therapy that binds the EGFR and prevents cell proliferation and metastasis were assessed in an HPV HNSCC cell line coculture assays with natural killer (NK) cell and dendritic cell (DC; ref. 44). Combination treatment enhanced the immunomodulatory effects of cetuximab, leading to increased NK-cell activation and DC modulation against the tumor cells. Furthermore, administration of CDN significantly improved survival in the murine models of HNSCC, despite the absence of STING, highlighting that STING may represent an effective therapeutic target regardless of the constitutive levels of the protein.

Differential STING expression in HPV+ and HPV HNSCC human tissue samples, publicly available in The Cancer Genome Atlas (TCGA) reveal that both the protein and mRNA levels of STING were significantly upregulated in HPV+ HNSCC compared with HPV-unrelated samples, but their expression levels do not correlate with the stage of disease or patient survival (44). We performed deeper analysis of the publicly available TCGA data (45), assessing STING expression within the dataset, comprising 279 HNSCC specimens (36 HPV+ and 243 HPV samples from four different primary tumor sites). Our analysis highlighted that STING mRNA expression is significantly upregulated in HPV+ HNSCC samples (Supplementary Fig. S1A). We also investigated STING expression in the 33 samples derived from the oropharynx (Supplementary Fig. S1B) as approximately 70% of all diagnosed OPSCCS are HPV+ (46). STING mRNA expression was again found at significantly higher levels in the HPV+ samples compared with the HPV OPSCC specimens. Cumulative evidence highlighting significant increases in both STING expression and activation in HPV+ HNSCCs indicates that this pathway is involved in producing the unique properties of this cancer phenotype. However, it is not clear whether putative STING expression offers adjuvant benefit for treatment or allows us to stratify patients that may be responsive to chemoimmunotherapy. Furthermore, it is not known whether patients with HPV-driven disease, originating outside the oropharynx, have the same survival advantage as seen in patients with OPSCCs (47). Further exploration is required to determine the true effects STING upregulation has on the tumor microenvironment, and its capacity to transform “cold” tumors into “hot.”

One theory postulates that STING is a determinant of tumor immunogenicity, with higher expression evoking powerful immune responses against the cancer cells (48). Recent studies favor this theory by reporting reduced T-cell tumor-specific responses following the knockout of STING in murine models (40, 49). Treatment with STING agonists have been shown to promote the infiltration of cytotoxic T cells into the tumor microenvironment (50, 51) and reversal of macrophage-mediated tumor immunosuppression (52). Initial HPV infection of the noncancerous cells has also been suggested to induce immune cell responses that are maintained even after the development of HNSCC (33). Numerous studies have observed that higher numbers of infiltrating and circulating T cells in HPV+ HNSCC provide better prognosis than HPV tumors (53–55), indicating that both systemic and local immune responses are important to provide better outcome, observed in HPV+ patients. However, results from the phase III KEYNOTE-040 study provide conflicting evidence for increased immunogenicity in HPV+ HNSCC (56). In recurrent/metastatic patients the HPV+ cohort failed to respond to pembrolizumab, an antiprogrammed cell death protein 1 (PD-1) antibody, whereas HPV patients demonstrated improved responses when compared to other standard-of-care options. This suggests that HPV may not always produce a highly immunogenic environment, and this may be a much more heterogenous group of tumors than initially anticipated, also opening avenues of investigation into whether the virus may mediate the degradation of STING (discussed in the next section). Furthermore, higher infiltration of immune cells commonly observed in HPV+ tumor microenvironments may also not reflect an accurate portrayal of STING expression in human tumor samples. IHC scoring of clinical specimens is assessed across tumor sections that generally represent the overall microenvironment. Immune cells can have high levels of STING (48), suggesting that the true cancer cell–specific expression of STING may be misconstrued across highly infiltrated HPV+ samples. This problem is further encountered with bulk RNA sequencing (RNA-seq), as STING mRNA expression is contributed by both the tumor cells and infiltrating immune populations. These methodologies are not sensitive enough to validate the cellular origins of STING, suggesting that the higher levels of STING associated with HPV+ tumors may be contributed by multiple sources. To overcome these limitations, future studies must rely on more extensive techniques such as single-cell RNA-seq and multiplex IHC to validate the true signal from cancer cells.

Another question that remains unanswered is whether downregulated STING observed in HPV-unrelated HNSCC allows immunologic escape of the tumor cells. Type-I IFNs are critical for effective immunosurveillance (57, 58) and are thought to play an important role bridging innate and adaptive antitumor immune responses by inducing upregulated antigen presentation on DCs that stimulates tumor-specific effector T cells (59). Evidence of STING-dependent IFN production that mediate the expansion and priming of CD8+ T cells provides further support for this theory and the importance of STING in the production of antitumor responses (39, 40, 60). Because HPV HNSCC are much more difficult to treat than their HPV+ equivalent, the potential lack of immune involvement in the microenvironment may assist much faster rates of HPV tumor progression.

Despite the increased numbers of infiltrating immune cells reported in HPV-associated tumors, the virus could also create a highly immunosuppressive environment, most likely by reducing innate immune recognition receptors, upregulating levels of PD-L1 (61), and/or downregulating MHC class I and II (62). Emerging evidence of HPV interference at the transcriptional level of cGAS-STING, and other innate immune sensing pathways, such as Toll-like receptor and RIG-1–MAVS pathways (63), provides further understanding of immune evasion strategies employed by the virus to facilitate tumorigenesis. Lau and colleagues initially reported that HPV18 E7 inhibited the cGAS–STING pathway, in a potent and specific manner, by reducing IFN responses to DNA stimulation (64). Although there was no evidence for direct binding of E7 to STING, the highly conserved LXCXE motif was found to be essential for this blockade. Several DNA virus oncoproteins, including HPV16 E7 (65, 66) and adenovirus E1a (67), contain an LXCXE protein motif that is necessary for high-affinity binding and inhibition of the Rb tumor suppressor protein (68). HPV16 E7 has also been found to specifically interact with STING via the LXCXE motif and block downstream signaling in HPV+ HNSCC cell lines (69). Dual removal of HPV16 E6 and E7 with CRISPR/Cas9 fully restored STING activity in HPV+ cell lines where E7 deletion alone did not (70), suggesting the two oncogenes have a synergistic effect that dampens STING-dependent type-I IFN production in HPV-related HNSCC.

Normal regulation of STING can be mediated through autophagy-dependent degradation (71, 72). In HNSCC cell lines, HPV16 E7 interacts with NLRX1, a mitochondrial-localized immune system regulator, which in turn destabilizes and facilitates the autophagic degradation of STING, resulting in reduced type-I IFN production and tumor-infiltrating lymphocytes in HNSCC murine models (73). Similarly, sex-determining region Y-box 2 (SOX2) has also been implicated in the autophagic degradation of STING and diminished type-I IFN signaling, although this appears to occur irrespective of the HPV status in HNSCC cell lines (74). SOX2 is a transcriptional regulator involved in maintaining the pluripotency of stem cells (75) and has been identified as an oncogene in over 25 cancers (76). Positive prognostic effects have been associated with increased SOX2 in both HPV+ and HPV HNSCCs (77, 78), but numerous studies indicate that SOX2 has a “stemness” effect on the tumor cells that has been linked to tumor progression (79). SOX2 upregulation degraded the levels of STING, forming an immunosuppressive environment, with reduced numbers of M1-like macrophages and increased regulatory T cells that promoted tumor growth (74). Overall, autophagy-dependent STING degradation may be a common strategy employed by both HPV and the tumor itself, to diminish STING-dependent type-I IFN immune activation (Fig. 1).

Epigenetic silencing and suppression have been proposed to regulate STING at homeostasis and is exploited by a variety of cancers to evade immune detection (80). Although E7-dependent epigenetic silencing of STING is yet to be investigated in the context of HNSCC, E7 has also been shown to epigenetically silence STING and RIG-1 in HPV-related cervical cancer epithelial cell lines, HeLa and CaSki (81). In these cell lines, E7 induced the upregulation of the histone H3 lysine 9 (H3K9)–specific methyltransferase, SUV39H1, which contributes to chromatin repression at the promotor regions of these immune sensors, diminishing both STING expression and type-I IFN production (81). Removal of HPV16 E7 in HPV+ HNSCC cell lines also restored potent IFN production in response to DNA stimulation, a phenomenon that remained absent in the HPV-expressing phenotype, demonstrating HPV-mediated regulation of type-I IFN responses (70). Furthermore, the presence of LXCXE-like motif structure, reported to suppress in STING, in chromatin regulator and histone modifier proteins supposedly aids in their interactions with pRB (82) and likely with STING to enable effective repression. Thus, LXCXE-like structures may be drivers of powerful inhibitory effects on STING that inadvertently facilitate tumor progression in both HPV+ and HPV HNSCC phenotypes.

The actions of HPV16 E7, aided by other HPV oncogenes, seemingly demonstrate a complex role in suppressing STING in HNSCC. Although HPV-induced STING inhibition and degradation are expected to result in reduced levels of STING in HPV+ tumors, primary clinical samples from HPV+ patients with HNSCC reveal enhanced levels of STING (41, 44). This discrepancy could partly be attributed to the studies describing the inhibitory effects of HPV16 oncogenes on STING, being performed in established HNSCC cell lines and not primary tumors. Furthermore, findings from cell lines are unlikely to comprehensively reflect the effect HPV on STING expression and activity in vivo, in the context of the largely heterogenous human tumor microenvironment. This opens the question as to how much insight cell line studies truly provide, and that additional work is required to validate the impact HPV16 has on STING and immune activation in HNSCC tumors.

Numerous clinical trials are now investigating the use of STING agonists alone or in combination with T-cell checkpoint inhibitors in a variety of solid tumor microenvironments. Pembrolizumab and nivolumab are the most common PD-1 inhibitors routinely used to treat metastatic or recurrent HNSCC (83), but limited overall response rates have been reported with single-agent administration in both HPV phenotypes (84). Type-I IFNs can increase the expression of PD-1 on effector T cells (85), suggesting that simultaneous STING activation could greatly improve the efficacy of anti–PD-1 immunotherapy. Preliminary results from several phase I and II trials report the efficacy (clinical activity) of approximately 10 synthetic CDN compounds (86) with efficacy of a STING agonist, ADU-S100 in combination with pembrolizumab currently being assessed for the treatment of PD-1 positive metastatic or recurrent HNSCC (NCT03937141). ADU-S100 in combination with either PD-1 (NCT03172936) or CTL-associated protein 4 (CTLA4) inhibitors (NCT02675439) is also being assessed in a phase I trial in a multitude of advanced metastatic solid tumors. The results obtained thus far demonstrate that patients have good tolerance to the treatment with some clinical activity observed, particularly in PD-1–positive breast cancer and refractory melanoma (87). Treatment with another STING agonist, MK-1454 (NCT04220866), intravenously administered with or without pembrolizumab, in HNSCC is also currently in a phase II trial with results projected in the next couple of years.

Majority of STING agonists currently in trial stages are synthetic CDNs that are delivered by intratumoral injection to the tumor microenvironment. This restricts their use to patients with accessible solid tumors and limits delivery to distal metastases. Several STING agonists that can be systemically administrated have recently been identified to overcome this problem. MAVU-104 is a novel, orally available drug that enhanced STING signaling and immune responses when delivered both intratumorally and orally in mice (88). Another orally available, STING agonist, MSA-2 undergoes dimerization in the acidity of the tumor microenvironment, thereby allowing the compound to preferentially enter and activate STING within tumor cells (89). MSA-2 has been reported to synergize with anti–PD-1 therapy to generate STING-dependent antitumor effects in mice models. The identification of efficacious systemically administered STING agonists is promising in the search for drugs that will produce widespread potency against all tumor sites. Developing these further could have significant effects on regression in the case of HNSCC, as patients commonly present with advanced metastases and/or develop recurrent disease. There is potential for systemically administered STING agonists to enter clinical trials in the near future, with the aim of demonstrating effective antitumor responses without precipitating a damaging cytokine storm in the process.

Most STING agonists currently being assessed in clinical trials have anionic properties that make it difficult for them to permeate the membrane and effectively interact with STING in the cytosol. To circumvent this issue, drug delivery systems utilizing biomaterials such as liposomes, polymers, and hydrogels have been developed to improve cytosolic delivery of STING agonists and subsequent clinical responses (86). The majority of studies have delivered encapsulated STING agonists by intratumoral injection, but certain studies are exploring the potential to develop systemic administrations (90). The use of drug delivery systems has shown enhanced retention of STING agonists at tumor sites, improved antitumor responses and colocalization with innate and adaptive immune cells (86). Polymer delivery has also demonstrated the ability to synergize in vivo with established immune checkpoint therapies (91). None of these drug delivery methods have yet entered clinical studies, but their ability to improve immune responses and survival in mice models compared with administration of the STING agonist alone suggests this may be an effective method to induce potent responses across the majority of patients. However, upregulated STING signaling has also been associated with advancing cancer, through mechanisms that promote tumor development via inflammatory-driven carcinogenesis and metastasis (92). Sustained release of cytosolic DNA, induced by tumor cell chromosomal instability, leads to chronic activation of STING and the downstream pathway that promotes tumor development (93). Metastasis in the brain can advance following the development of specific carcinoma-astrocyte gap junctions that permit tumor cell–produced cGAMP transfer to surrounding cells that establish an inflammatory environment (94). This highlights the necessity of a fine balance between generation of productive antitumor immune response while avoiding damaging overactivation.

HPV-associated cancers have been characterized in all HPV-infecting areas of the body. The incidence of the majority of these cancers is continuing to rise and significant reduction due to the introduction of preventative HPV vaccines is not estimated to be observed until 2060 (95). Improved understanding of the role STING plays in HPV-related cancers may allow the development of personalized approaches to treatment. In particular, STING activity may help identify patients that are responsive to established therapies, by providing an adjuvant effect with STING agonists. Further characterization of HPV within HNSCC may also open avenues to investigate viral mechanisms involved in the development of a variety of cancers. For example, clinically significant HCMV reactivation is common in patients with follicular lymphoma following immunosuppressive therapy. Although HCMV has been detected in many tumors (96–98), it is not usually detected in healthy tissues surrounding HCMV+ tumors (99), indicating opportunistic viruses may exploit immune surveillance mechanisms within the tumor microenvironment to enhance tumor survival through mechanisms that are distinct from classic tumor growth and metastasis. This may also be relevant in tumors that are driven by HPV affecting the anus, vulva, vagina, and cervix or in tumors driven by EBV such as nasopharyngeal carcinoma, gastric carcinoma, and Hodgkin lymphomas (100). Currently not considered in the pathogenesis model of such tumor microenvironment with virus activity is the understanding of innate immune pathways that regulate viral infections such as the STING. Novel understanding of mechanisms involved in viral commandeering of innate immune system pathways in the tumor microenvironment will help us identify challenges in the treatment of such tumors, design new therapies and allow stratification of patients that may benefit from a particular treatment modality.

No disclosures were reported.

E. Saulters is supported by the University of Liverpool, Institute of Translational Medicine Cancer Research Endowment studentship. L.N. Dahal is supported by Northwest Cancer Research (NWCR) underpinning research grant and NWCR research development fund.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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