Cells determine their function through signaling pathways and communication with other cells and their microenvironment. Due to ligands’ binding to their receptors on the cell surface, protein cascades are activated and consequently affect the level of gene transcription, leading to the conversion of external stimuli into biochemical signals. These signaling pathways control biological effects such as proliferation, differentiation, and death; thus, disrupting these pathways leads to malignancy [1]. Also, they are owing to changes in some critical cell proliferation and apoptosis-controlling pathways, including phosphatidylinositol 3-kinase (PI3K)/phosphorylation of protein kinase B (AKT), extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK), Notch, Wnt/β-catenin, and epidermal growth factor receptor (EGFR). In addition, a variety of inhibitory immune checkpoint molecules, such as programmed cell death protein 1 (PD-1, CD279) and its ligand PD-L1 (CD274), have been playing a significant role in various types of cancers and chronic viral infections [1–3]. For instance, it was demonstrated in a report published on the PD-1/PD-L1 axis in acute viral infections affecting the lower respiratory tract that this pathway impairs the activity of CD8+ T-cells in the human respiratory system. In addition, dendritic cells inhibit T-cell function in acute viral infections by highly expressing PD-L1 on their surfaces [3]. PD-1, on the other hand, is expressed in lymphocytes, specifically CD8+ and CD4+ T-cells, and is an inducible negative regulator of T-cell activity; as a result, PD-L1 is one of two PD-1 ligands found on antigen-presenting cells (APCs), peripheral tissues, and cancerous cells [4]. As a result, the interaction of PD-1/PD-L1 leads to the activation of inhibitory signals in T-cells, which eventually leads to the destruction of T-cells, anergy, and reduced function [5,6]. PD-1 causes regulatory T-cells to face less apoptosis while increasing the death of some T-cells in lymph nodes. On the surface of CD8+ and CD4+ T-cells, PD-1 is more apparent. The PD-1/PDL1 pathway reduces the activity of T-cells; this inhibitory effect is done by binding PD-1 to its ligands (PD-L1 and PD-L2), which are produced on the surface of cancerous cells and peripheral tissues. The expression of PD-L1 also regulates IFN-γ-secreting T-cells [3]. Moreover, it has been illustrated that the interaction of PD-1/PD-L1 can increase the transcription of several genes involved in cancer induction. Cancer cells express immune system regulators such as the cluster of differentiation (CD)-47 and PD-L1 to induce immune response resistance. Also, cellular myelocytomatosis (c-MYC) activation is due to CD-47 and PD-L1 expression [4]. Because c-MYC can directly bind to the CD-47 and PD-L1 gene promoters, inhibiting c-MYC reduces the expression of both genes (CD-47 and PD-L1) and thus improves the anti-tumor immune response [7]. It is hypothesized that T-cell apoptosis is associated with c-MYC overexpression, a critical target gene of the Wnt/β-catenin signaling pathway [8]. Additionally, Wnt/β-catenin signaling has been implicated as one of the primary inducers of cancer, accelerating the development of the disease through controlling the tumor immune cycle in various cell types, including dendritic cells, T-cells, and tumor cells [4]. Some significant regulators of the anti-tumor function of T-cells, especially effective T-cells, T helper cells (Th), and regulatory T-cells (T-reg), are changed functionally by abnormal Wnt/β-catenin signaling [4]. Besides, the activation of the Wnt/β-catenin signaling pathway is observed during various types of malignancies, such as hepatocellular carcinoma, human immunodeficiency virus (HIV), breast cancer, as well as in HPV-related cancers such as oropharyngeal and cervical cancers, head and neck, anal cancer, and vulvar cancer [1]. As mentioned above, increased levels of PD-1 expression on the T-cells and APC cells, and also hyper-activation of the Wnt pathway during chronic HPV infection, are positively associated with tumor cell metastasis and HPV-associated cancers such as cervical cancer and cervical intraepithelial neoplasia (CIN) grade [1,9]. Besides, inhibition of the Wnt signaling pathway in cancer cells could disrupt the expression of CD-47 and PD-L1, resulting in an increased immune defense against tumors [8]. In other words, MYC signaling leads to increased expression of CD47 and PD-L1 in tumor cells. Meanwhile, due to CD47-SIRPα interaction, the phagocytosis activity of tumor cells by macrophages and dendritic cells is disturbed. As a result, the lack of activity of the innate immune system may cause an increase in the recruitment of T-cells to the tumor microenvironment. In contrast to PD-L1 expression, it may disrupt in the function of T-cells in the tumor microenvironment. In addition, the Wnt/β-catenin signaling pathway may affect MYC activation [10].

The present study hypothesized that current research concentrates on the Wnt/β-catenin and PD-1 signaling pathways, crucial elements in cancers, particularly cancers related to viruses. These findings may alter the manner that individuals evaluate cancer patients and immunotherapy (Fig. 1).

During infection, the PD-1/PD-L1 signaling axis and Wnt play an essential role in developing and maligning epithelial cells. Thus, after presenting the antigen to the T-cells, the DC cells induce signaling pathways in T-cells, resulting in the induction of TCR and the secretion of pro-inflammatory cytokines. Then these cytokines lead to the expression of PD-1 on the surface of T-cells. In this line, Wnt binds to its receptors. The integrated HPV genome regulates these pathways to increase escape and inhibit the immune response against tumor cells by expressing E6 and E7 oncoproteins. Also, these oncoproteins lead to the induction of a series of cellular signaling pathways of Wnt; it eventually conducts the expression of the c-MYC in the target cell nucleus. The c-MYC gene leads to increased expression of PD-L1 and CD47 at the surface of tumor cells. By binding PD-L1 to PD-1 expressed at the surface of T-cells, it leads to apoptosis, anergy, and ultimately inhibition of the immune response vs. tumor cells. Also, INF-γ secreted by T-cells leads to increased PD-L1 expression at the surface of tumor cells.

In 1991, the term Wnt was coined from the acronyms homologous wingless (WG) and INT1, which refers to a group of genes that encode secretory glycoproteins [11]. 11 receptors of the Frizzled (Fz) family in humans could activate the Wnt signaling pathway, such as Fz1 to Fz10, Smo, and two low-density lipoproteins receptor-related protein (LRP) 5 and 6 [12]. Wnt ligands activate three active signal transduction pathways, including the canonical Wnt/β-catenin pathway and two non-canonical pathways [13]. According to studies, the Wnt/β-catenin signaling pathway is crucial for cell growth, proliferation, differentiation, adhesion, and polarity [11,14–16], as well as for carcinogenesis from the initial stages to the advanced parts in a variety of neoplasms [17].

The β-catenin accumulation due to the Wnt pathway’s abnormal function is observed in the cytoplasm [18]. Indeed, the binding of Wnt to Fz and low-density lipoprotein receptor-related protein 5/6 (LPR5/6) receptors results in the accumulation of β-catenin in the nucleus and cytoplasm; after Fz dimerization by LRP5/6 co-receptor, the intracellular motif of Fz leads to the absorption of cytoplasmic protein Dishevelled (Dlv) [19]. Then, the LPR5/6, phosphorylated by CK1 and AXIN, binds to the β-catenin destruction complex that eventually prevents the β-catenin destruction that these mechanisms use to promote nuclear β-catenin transfer [18,20–22].

The β-catenin then enters the nucleus as a transcription co-activator, resulting in activated transcription via the complex of transcription factors such as T-cell factor (TCF)/lymphoid enhancing factor (LEF) [17]. In the nucleus, β-catenin binding to TCF/LEF conducts the separation of co-receptors, including Groucho/TLE; as a result, it interacts with co-activators such as cell cycle-related and expression elevated protein in tumor (CREPT), four-and-a-half-LIM-domain 2 (FHL2), and CREB-binding protein (CBP/p300) and remodelers of chromatin such as brahma-related gene 1 (Brg-1) [21,23–29].

Some β-catenin in the cytoplasm are affected by proteasome degradation. During this process, the AXIN scaffold protein controls the process of β-catenin degradation by utilizing important proteins such as glycogen synthase kinase-3β (GSK-3β), casein kinase 1 (CK1), adenomatous polyposis coli (APC), Yes-associated protein (YAP)/Transcriptional co-activator with PDZ-binding motif (TAZ), and beta-transducing repeat-containing protein (β-TrCP) [30–33]. APC inhibits PP2A phosphatase-mediated β-catenin dephosphorylation [34]. It has been demonstrated that the recurrence of E3 β-TrCP ubiquitin ligase by the YAP/TAZ complex and the detection of serine (Ser) or threonine (Thr) phosphorylation by E3 β-TrCP ubiquitin ligase cause the increase in ubiquitination of β-catenin and its subsequent proteasomal destruction [33].

Furthermore, other factors that participate in tumor-genesis, including c-MYC, metalloproteinase 7 (MMP-7), and the vascular endothelial growth factor (VEGF), are stimulated by the β-catenin/TCF-LEF complex [35]. Following the above interactions with catenin, various genes such as c-JUN and Cyclin D1 are expressed, which leads to the regulation of polarity, proliferation, and differentiation of various cellular genes in the development of malignancy [29].

PD-1, as an inhibitory co-stimulant receptor and a member of the CD28 family, is expressed in innate and acquired immune cells and regulates inflammation and self-reactivity [36]. Also, as an inhibitory receptor in T-cells, PD-1 has been associated with T-cells malfunctioning during infectious diseases and malignancies [37]. This inhibitory molecule contains two types of ligands from the B7 family on the cell surface, including PD-L1 (B7-H1) and PD-L2 (B7-DC), which have different expression patterns [38–41]. It is a kind of type 1 transmembrane receptor of the immunoglobulin super family [38]. In many tissues, PD-L1 is expressed on the surface of immune cells such as T-cells, B cells, dendritic cells (DC), macrophages (MQ), and non-hematopoietic parenchymal cells. PD-L2, however, is only expressed on the antigen-presenting cells’ surface, including DCs, MQ, B cells, and many tumors [42–46]. It has been speculated that the regulation of primary T cell function in lymphatic organs and the control of inflammation and autoimmunity in peripheral tissues is achieved by binding B7 family ligands to CD28 family receptors [37]. Moreover, gamma-chain cytokines such as IL-2, IL-7, and IL-15 promote the expression of PD-1 on the surface of monocytes, macrophages, and T-cells [37]. Granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-gamma (INF-γ), and IL-4 also regulate the expression of PD-L1 and PD-L2 on the surface of macrophages; among these; IL-4 and GM-CSF, have a significant role in the expression of PD-L2 [47,48]. Meanwhile, interferon regulatory factor-1 (IRF-1) binding to the PD-L1 gene promoter is regulated by downstream IFN-γ signaling [49]. It has been demonstrated that mechanisms such as INF-γ production by lymphocytes in the tumor environment, genomic alterations, and the activation of carcinogenic signaling pathways increase PD-L1 expression in tumor cells [50,51].

Furthermore, in a study conducted by Dong et al. [52], in 2018, it was reported that overexpression of miR-18a in cervical cancer indicates an increase in PD-L1 levels by preventing phosphatase and tensin homolog (PTEN) (a PI3K-AKT pathway inhibitor), WNK2 (a MAPK inhibitor), and SRY-box transcription factor 6 (SOX6) (a type of Wnt/β-catenin inhibitor), activated PI3K/AKT, MAPK, and Wnt/β-catenin pathways and promoted the induction of PD-L1 [52]. Moreover, the evidence suggests that over-stimulation of the EGFR pathway seen in EGFR-induced cancers can lead to the expression of PD-L1 in human cancer cells [37,53]. The IFN-γ and EGFR have used Janus kinase 2 (JAK2) as standard signaling to transmit external or internal signals to tumor cells, respectively [54]. For example, in HPV infection individuals, PD-L1 expression is induced by EGFR and JAK2/signal transducer and activator of transcription 1 (STAT1)-dependent procedures; in particular, inhibition of JAK2 prevents re-regulation of PD-L1 in tumor cells, leading the increased immunologicity [54].

It has been denoted that in tumor cells, two main pathways regulate the expression of PD-L1. The first one is an “external” signaling pathway in which an anti-tumor cellular immune response drives INF-γ production via natural killer (NK) cells and CD8+ tumor-infiltrating lymphocytes (TIL). The produced INF-γ contributed to the expression of PD-L1 in tumor cells [54]. The second one is an “intrinsic” signaling pathway in which tumor-induced pathways within the tumor cells induce the over-expression of PD-L1 [55]. Given that the INF-γ produced by NK cells and T-cells is a well-known stimulus for PD-L1 expression, the complex signaling pathways of PD-L1 regulation must be adequately investigated. Regarding the PD-1 ligands that play a significant role in maintaining immune suppressive tumors, a set of PD-1 and PD-L1 expression and signaling control mechanisms are emerging [37,56]. Besides, it demonstrated that this molecule played a significant role in inducing and maintaining central and peripheral tolerance [57]. By presenting the viral antigen via DCs, a signaling pathway is induced through PD-1 on CD8+ T-cells; as a result, it leads to T-cells tolerance. In other words, PD-1 is called a “rheostat,” the T cell response’s threshold, power, and duration [58–60].

The HPV-specific immune response, as well as the destruction of HPV-infected cells in the cervical region, is initiated by T helper cells (CD4+), cytotoxic T-cells (CD8+), and dendritic cells (DC) [61]. As mentioned in the previous section, PD-L1 molecules are overexpressed on the surface of T-cells during viral infection, resulting in the induction of tolerance, inhibition of activity, and cytokine production [5,6].

On the other hand, the Wnt/β-catenin signaling pathway is critical for T-cells proliferation and differentiation; hence, activation of the TCF and LEF genes and the Wnt/β-catenin pathway in mature T-cells causes cytotoxic T cell maturation to be impaired [62]. In addition, the Wnt pathway activates Fra1, a target of the interleukin-17 (IL17RA) cytokine cascade [63,64]. IL-17A, produced by T helper 17 (Th17) cells in response to IL-23, stimulates of this pathway [65].

The following will describe the effect of each of these pathways on malignancy progression.

The disease state of HPV is related to the level of PD-L1 expression in such a way that in inflammatory cells infiltrating into the tumor, such as TILs, the level of PD-1/PD-L1 expression was higher in cervical cancer than in endometrial and ovarian adenocarcinoma [98]. As reported, in the PD-L1+ tumor environment, a higher number of tumor-infiltrating lymphocytes was associated with a better prognosis [98].

Tumor infiltrating lymphocyte (TILs) are one of the important components of the tumor immune microenvironment, and the quantity and function of these cells reflect the strength of the antitumor response [99–101]. Many quantitative studies have investigated the relationship between PD-L1 expression and TILs in the tumor immune microenvironment in cervical malignancy [102–104]. Feng et al. showed that in 10.0% of people with cervical cancer, the expression level of PD-L1 in TILs cells, and the secretion of inflammatory cytokines increased [105]. The evaluation of the quantity of TIL and its functional state can complement the level of PD-L1 expression in tumors since TIL can also predict the response to anti-PD-L1 therapy [106]. In cervical cancer, Karim et al. demonstrated that more than 50% of TIL expressed PD-1, and only 19% of tumor cells were PD-L1 positive [107].

Furthermore, although PD-L1 expression had no effect on patient survival directly, patients who had an overabundance of infiltrating regulatory T-cells survived longer with PD-L1-positive tumors [107]. D’Alessandris et al. reported in 2020 that stromal TIL cells have the more immunogenic potential for cervical cancer than CD3+/CD4+ helper T-cells. Also, they showed that during malignancies, 100% of immune cells and 92% of tumor cells express PD-L1 [108]. On the other hand, the number of cancer cells with PD-L1 was associated with an increase in TIL and PD-L1 expression in immune cells [108]. So, the expression of PD-L1 on the tumor cells’ surface, in addition to immune escape of cells, leads to the weakening of the anti-tumor immune response of TIL cells and, as a result, tumor progression [104]. In contrast, high PD-L1 expression in TILs is substantially associated with the existence of high TILs. It has also been demonstrated that high PD-L1 expression has a negligible association with age, tumor size, lymph node positivity, or histological grade. However, clinical trials are required to examine the impact of PD-L1 expression in the immune stroma to predict optimal treatment response [105].

Nevertheless, it was shown in the study by Goldsberry et al. [109] that there is an inverse association between the Wnt signaling pathway and TILs. This study examined the effect of neoadjuvant chemotherapy and the relationship between the Wnt signaling pathway and tumor-infiltrating lymphocytes in HGSOC [109]. Additional investigation is required to better understand the Wnt pathway’s role in immune regulation.

In the neoplasm progression trend, activated T-cells and NK cells in the tumor microenvironment (TME) released significant levels of IFN-γ [110], which leads to increased PD-L1 expression on the surface of cancer cells, subsequently enabling them to evade the immune system’s access [111,112]. Also, it has been shown that there is a strong parallel between increased PD-L1 expression and HPV infection [113]. The PD-L1 methylation pathway participates in suppressing gene expression and other cellular protein transcription in cervical cancer induced by HPV [113], and the PD-1/PD-L1 expression on tumor-infiltrating lymphocytes (TIL) in cervical cancer is more significant than in other malignancies [114].

According to the findings, numerous transcription factors, including c-MYC, STAT1, and STAT3, efficiently promote PD-L1 gene expression and the c-MYC gene is widely involved in various malignancies [7]. On the other hand, elevating the activity of the Wnt signaling pathway causes the expression of essential genes, including c-MYC (a regulator gene and proto-oncogene), Nanog (a transcription factor sustaining pluripotency of embryonic stem cells), Oct4 (octamer-binding transcription factor 4), Sox2 (sex-determining region Y-box 2), Snai1 (a zinc finger protein regulating epithelial to mesenchymal transition), and Twist (a primary helix-loop-helix transcription factor), to be increased, resulting in tumor development [115]. It has also been shown that during HPV infection, viral oncoproteins such as E5, E6, and E7 cause post-translational modifications in histones and influence the methylation state of cellular targets by influencing other cellular genes such as MYC, APOBEC3, and interacting with DNMT1 and other epigenetic modulators [64]. As a result, owing to the promotion of PD-L1 gene expression and Wnt signaling pathway activation, the progression of malignancy and tumor growth has been induced by HPV infection.

Human papillomaviruses are the double-stranded DNA viruses of the Papillomaviridae family. The capsid of these viruses is icosahedral, without envelope, and their genome has eight open reading frames (ORF) [116]. Papillomaviruses are epitheliotropic, dividing into mucosal and skin contaminants and classified into low-risk and high-risk varieties based on their ability to induce cancer and malignancy [117,118]. HPV-6 and HPV-11 are among the low-risk types that generate 90% of genital warts and rarely lead to malignancy [119,120]; however, HPV-16 and HPV-18 are high-risk types that cause 70% of cervical cancers [121].

Moreover, the World Health Organization (WHO) reported that cervical cancer is the fourth most common cancer among women and accounts for 30% of worldwide deaths [122]. Other malignancies associated with the virus include penis neoplasm, vulva, anus, anal, oropharyngeal, and head and neck cancer [123–126]. The papillomaviruses initiate proliferation by entering the target cells through damaged skin or mucosal squamous epithelium [127]. Thus, leading to cell division and genome replication by exploiting cellular DNA polymerase in basal cells, the infected cells are transported to the upper layers [128].

Furthermore, HPVs have two types of amplification: plasmid replication and vegetative replication [129,130]. It has also been recommended that the HPV DNA encode six early proteins (E1, E2, E4, E5, E6, and E7) and two late proteins (L1 and L2) [127] that through E5, E6, and E7 oncoproteins conduct malignancy and cellular transformation [4,65,131–133]. These oncoproteins, by accumulation in the nucleus and cytoplasm of target cells and interacting with cell pathways, lead to genomic inconsistency and result in malignancy by disrupting cell cycle controllers [134]. The stimulation of cellular signals via HPV oncoproteins after primary infection leads to the completion of viral replication and the constitution of infectious particles [1]. Also, the high expression of oncoproteins leads to the disruption of regular cell activity and stimulation of uncontrolled transformation. Interactions of E6 and E7 oncoproteins with different cellular pathways regulate signaling pathways and other mechanisms associated with HPV-caused cancers. These signaling mechanisms and pathways that are involved in persistent virus infection, such as, Hedgehog, Erk/MAPK, Notch, Wnt signaling pathways, PI3K/Akt, EGFR, and immune checkpoints, including PD-1 and CTLA-4, participate in differentiation and survival proliferation, cell cycle development [1,2,135–139]. However, the interaction of HPV oncoproteins and the PD-1/PD-L1 pathways, the regulation of the Wnt/β-catenin pathway by these oncoproteins, and their synergistic effect on disease progression, is still controversial [140].

Given the impact of approximately 30% of chemotherapy medicines on HPV carcinogenicity and recovery in individuals with cervical cancer, therapeutic methods such as HPV vaccination are essential to improve HPV16 and other hr-HPV infections and related malignancies [168,169]. Due to the promotion of mitosis and PD-L1 expression with increasing viral load, immunotherapy methods differ at various phases of HPV infection [61]. Several HPV therapies inhibiting the immune checkpoint have been developed to improve the vaccine’s effect on the carcinogenic process [170]. Nivolumab, pembrolizumab, and atezolizumab are monoclonal antibodies that target the PD-1/PD-L1 and CTLA-4 pathways as immunotherapy (fda.gov) [169,171]. It’s worth noting that PD-1/PD-L1 immunotherapy antibodies are related to higher numbers of tumor-infiltrating T CD8+ cells, reinvigorate anti-tumor immunity, and improve patient outcomes [172,173]. Despite this, Th17 cells and pro-inflammatory cytokine secretion like IL-17 have shown resistance to PD-1-based treatments [174–176]. In a study by Li et al. [175], in mice with lung cancer, high levels of IL-17 secretion were associated with resistance to PD-1-based therapies; additionally, it was discovered that blocking PD-1 in mice after neutralization of IL-17 as well as anti-PD-1 treatment reduced the size of cancerous tumors and increased the activity of T CD8+ cells [175]. Thus, following PD-1/PD-L1 inhibitors, glycolysis levels in cancer cells decrease, resulting in increased glucose in TME and T-cells activation [177]. Also, blocking PD-1 leads to improved CD4 TIL cell function, DC maturation, CD86 expression, and IL-12 secretion [92].

In addition to the PD-1/PD-L1 axis, the Wnt pathway is also associated with cancer metabolism and immunotherapy [115]. On this basis, it has been documented that RNA-interference (RNAi)-based therapies against the Wnt pathway increase the penetration of cytotoxic T-cells and consequently reduce tumor size [178]. It has also been observed that, by inhibiting the Wnt signaling pathway, resistance to PD-1 inhibitors and tumor cell growth is reduced [115]. Following the use of CPI, the T CD4+ and CD8+ cell lines’ functions increase due to PD-1 and PD-L1 expression and Wnt pathway activity in CD4+ and CD8+ TIL cells [115,179]. Also, the self-sufficiency of effector cells to TME, correlated with the classical Wnt active signaling pathway, contributes to cancer immunotherapy resistance [180]. In the absence of Wnt ligands, GSK3β, as a component of axin, causes the β-TrCP to degrade the PD-L1 phosphorylation-dependent proteasome and facilitate interferon-secreting CTLs to penetrate the tumor microenvironment [69]. On the other hand, the immune checkpoint inhibitor (ICI) reduces the ability of PD-1 and CTLA-4 receptors, which diminishes the penetration of CTLs and leads to a decrease in the therapeutic effect of ICI [69]. Moreover, the lack of CTLs has occurred in the active Wnt pathway tumor cells. It has been shown that the anti-CTLA4 monoclonal antibodies, in combination with canonical Wnt signaling inhibitors may prevent cancer progression in mice samples [181]. In this regard, combination therapy following the use of immune checkpoint inhibitors and anti-Wnt signaling pathway, has been shown to be effective in enhancing the therapeutic effect of malignancies [115]. Moreover, interference with GSK3 inhibitors has also been found to cause T CD8+ and Th17 cells to differentiate into anti-cancer stem cells [182,183]. Notwithstanding the effect of anti-tumor activity of antibodies against immune checkpoints, such as pembrolizumab, in HPV16+ individuals with PD-L1+ tumor cells, they had more effectiveness in combination with radiotherapy, chemotherapy or therapeutic vaccines [113]. Despite the efficacy of anti-PD-1/PD-L1 treatments, adverse effects are observed in a limited percentage of patients [184]. As a result, predictive biomarkers determine whether patients are eligible for this treatment and predict clinical outcomes [185]. For instance, in cervical cancer, inhibiting PD-1 causes T-cell exhaustion to be reversed. Despite inhibiting PD-1/PD-L1, several checkpoint molecules, including TIGIT and Tim-3, have a role in T and NK cell depletion [186,187]. Thus, the expression of PD-1 on the surface of CTLs during cervical cancer can be a crucial determinant in predicting the efficacy of PD-1 blockade therapy [188]. This therapy technique has significant adverse effects due to the immunological tolerance process and the efficiency of inhibiting immune checkpoints [184]. Immunogenicity and poor permeability of tumor tissues are both disadvantages of antibody medicines, which delay the response of PD-1/PD-L1 antibody therapies [189,190]. As previously stated, immunosuppressive therapy causes the reactivation of T-cells, resulting in tumor mortality in the mouse model; also, peptide immunization causes T-cells to reactivate and destroy tumors [184].

Generally, immunotherapy is often safer than other forms of oncology treatment, such as radiation, chemotherapy, and surgery, since it is non-invasive and relies on the ability of autoimmune cells to resist neoplasia [191]. Besides, because immune checkpoint inhibitors are particular to the target cell, they have few adverse effects [192] (Table 1).

The development of the tumor microenvironment enhances dendritic cell signaling and type 1 interferon release. In addition, chemokines cause T CD8+ cells to infiltrate and exert authority in the TEM, followed by the production of PD-L1, IDO, Treg cell infiltration, and anergy, all of which suppress T CD8+ cells [214], and correlate to a decrease in immunosuppressive pathways [215]. Also, the native immune phenotype is inhibited by the reduced expression of inflammatory T-cell genes in tumor cells compared to normal tissue [216]. A recent study published in the cancer genome atlas (TCGA) database found a negative correlation between the expression of inflammatory genes in T-cells and tumor cells, with one of the potential mechanisms being stimulation of the Wnt/β-catenin pathway [216]. Moreover, invasive features such as lymph node metastasis or angiogenesis are associated with the up-expression of PD-1, PD-L1, and CD8; their identification could be a diagnostic marker in cervical cancer tissues [217]. As mentioned, the PD-1/PD-L1 pathway leads to the dysfunction of cytotoxic T CD8+ cells, which is a barrier to cancer treatment, and this pathway leads to the escape of tumor cells from the immune system [157]. Ultimately, given the role of the mechanisms and pathways of Wnt/β-catenin and PD-1/PD-L1 in carcinogenesis and tumor formation, both of these pathways, by affecting the c-MYC gene and consequently deactivating the functions of the T CD8+ cell, lead to tumor cells escaping from the immune system and ultimately resistant viral infection. This information can also provide a new strategy for diagnosis and the development of effective treatments.