The Tumor Microenvironment Remodeled by Epstein–Barr Virus: From Primary Site to Distant Metastatic Niche

Abstract

Epstein–Barr virus (EBV) is one of the most pervasive viruses worldwide, and EBV infection is inextricably linked to a multitude of lymphoid and epithelial neoplasms. EBV is responsible for the advancement of malignant disease by modifying the tumor microenvironment (TME), which is a sophisticated and evolving system that facilitates tumor growth, invasion, and metastasis. EBV infection has a profound impact on the cellular and noncellular components that constitute the TME. Our review presents a summary of the composition of the EBV-remodeled TME, with a particular focus on EBV-induced functional phenotypes in non-tumor cells. Furthermore, we discuss the potential for reversing EBV-driven TME remodeling as a therapeutic strategy for treating the malignancies associated with EBV infection.

1. INTRODUCTION

Epstein–Barr virus (EBV) is a globally widespread viral pathogen,¹⁾ with an estimated prevalence of over 90% in the global population.²⁾ As a member of the Gammaherpesvirinae subfamily, EBV is also designated as human herpesvirus 4 (HHV4).³⁾ In 1964, it was the first viral pathogen to be identified as the cause of Burkitt’s lymphoma (BL).^4–6) EBV has been associated with other malignant conditions, including nasopharyngeal carcinoma (NPC),⁷⁾ gastric cancer (GC),⁸⁾ Hodgkin’s lymphoma (HL),⁹⁾ and lung carcinoma.¹⁰⁾ Additionally, recent evidence has indicated a potential correlation between EBV infection and breast cancer.³⁾

As a complex and dynamic system, the tumor microenvironment (TME) comprises a multitude of cellular and non-cellular components, including immune cells such as B cells, T cells, macrophages, and natural killer cells (NK cells); stromal cells such as fibroblasts and endothelial cells; tumor cells themselves; the extracellular matrix (ECM); and signaling molecules that mediate cell-to-cell communication.^11–17) The capacity of immune cells within the TME to either promote or inhibit tumor growth is contingent upon their phenotype and activation status.¹⁷⁾ The ECM plays a role in regulating tumor growth, invasion, and metastasis.¹⁸⁾ Tumor cells interact with surrounding stromal cells, influencing their biological behavior and thereby creating a supportive niche that facilitates tumor growth and survival.^19,20) The progressive evolution of the TME not only drives tumor progression but also determines the response to cancer therapy.^21,22)

EBV is capable of surviving, replicating, and spreading from the local microenvironment by infecting host cells. EBV affects the functionality of multiple cellular activities within the TME, including immune cell infiltration, cytokine production, angiogenesis, and ECM remodeling. The remodeling of the TME provides a supportive environment for tumor immune evasion and resistance to therapy, which ultimately contributes to the development of distant metastasis.^23,24) Our review presents a summary of the late evidence regarding how EBV remodels the TME and the underlying signaling pathways. Furthermore, we examine the implications of these recent advances for developing personalized therapies for EBV-associated malignant diseases.

2. COMPOSITION OF THE TME IN EBV-ASSOCIATED TUMORS

2.1. Cellular Components

2.1.1. EBV-Infected Tumor Cells

Tumor cells that originate from lymphatic or mucosal epithelium and are infected with EBV typically exhibit malignant transformation and an uncontrolled growth potential. These cells express a variety of viral proteins, including latent membrane proteins (LMPs) and Epstein–Barr nuclear antigens (EBNAs), which promote the proliferation, survival, and immune evasion of EBV-infected cells. Furthermore, infected tumor cells carrying the EBV genome modulate the phenotypes of surrounding non-infected cells by releasing various EBV-relevant signaling molecules, including EBV-encoded microRNAs (miRNAs), LMPs, and EBNAs.

2.1.2. Non-EBV-Infected Cells

The TME is comprised of a heterogeneous population of immune cells, including B cells, T cells, NK cells, macrophages, and dendritic cells (DCs). Immune cells are responsible for the clearance and destruction of EBV-infected tumor cells. However, these cells also establish an immunosuppressive environment, thereby providing regional support for tumor growth and invasion. In other words, the effects of immune cells on tumorigenesis are dependent on the manner of assembly of the cell types, their activation state, and local-regional signals that mediate cell-to-cell interplay. The immune component of the TME, which is modulated by interleukins (ILs) and chemokines, exhibits numerous similarities between EBV-positive and EBV-negative tumors.^25,26) Nevertheless, the EBV-remodeled TME contributes to the unique malignant characteristics of EBV-infected cells, enabling EBV-positive tumors to become proliferative, invasive, and eventually metastasize remotely. The Graphical Abstract figure illustrates the intricate cellular composition of the TME in EBV-positive human cancers.

2.1.2.1. T Cells

T-cells play a pivotal role in the TME as key immune components, being recruited by the tumor cell-produced chemokines. The number of T cell subsets varies depending on the specific type of EBV-associated tumor and between individual cases with the same tumor.

In comparison to EBV-negative tumors, EBV-positive tumors demonstrate an increase in the number of CD8+ T cells.^27–29) CD8+ T cells are capable of selectively recognizing and killing EBV-infected tumor cells. An increased number of CD8+ T cells is associated with a higher proportion of effector T cells, which produce cytotoxic molecules. Furthermore, elevated CD8+ T cell levels are linked to diminished activation of the Wingless/Integrated/β-catenin and transforming growth factor-β (TGF-β) signaling pathways.³⁰⁾ To evade detection by CD8+ T cells, EBNA1 downregulates the expression of human leukocyte antigen I (HLA I) on the surface of T cells, thereby impeding antigen presentation.³¹⁾ It has recently been demonstrated that increased numbers of exhausted CD8+ T cells from either the TME or peripheral blood result in a reduction in the cytotoxic activity of CD8+ T cells in EBV-positive tumors.^32–34)

CD4+ T cells play a pivotal role in the immune response, primarily through the promotion of B-cell maturation, antibody production, and the provision of assistance to CD8+ T cells. CD4+ T cells can be further classified into distinct subsets, including T-helper 1 (Th1), Th2, Th17, and regulatory T (Treg) cells. The number of Th2 and Treg cells is observed to increase in the TME of EBV-associated tumors.³⁵⁾ The predominant T cell subsets within the TME in EBV-associated Hodgkin’s lymphoma are Th2 and Treg cells.³⁵⁾ Conversely, a higher frequency of Treg cells has been documented in EBV-associated NPC.³⁶⁾ However, the effects of these traits of CD4+ T-cell distribution on the alteration of the tumor immune microenvironment are still not well understood.

2.1.2.2. Myeloid-Derived Suppressor Cells (MDSCs)

MDSCs derived from immature myeloid cells can differentiate into mature cells, such as macrophages, DCs, and granulocytes.³⁷⁾ MDSCs promote the formation of Treg cells and attract them to the TME, leading to immunosuppressive effects.^38–40) MDSCs facilitate the differentiation of naive CD4+ T cells into Treg cells by releasing retinoic acid and TGF-β, thereby promoting the transdifferentiation of Th17 cells into Treg cells.³⁸⁾ MDSCs induce the immunosuppressive activity of Treg cells by regulating the production of IL-10 and interferon (IFN)-γ.⁴⁰⁾ The peripheral blood of patients with EBV-positive tumors, including NPC,^41,42) Hodgkin’s lymphoma,^43,44) and gastric cancer^45–47) has been shown to contain significantly elevated levels of highly expanded MDSCs. MDSCs are often seen in the stroma of NPC and gastric cancer.^41,47–49)

Tumor-associated macrophages (TAMs) are defined as the macrophages that are attracted to and recruited into the TME by chemokines, including chemokine (C-C motif) ligand (CCL) 2, namely monocyte chemoattractant protein-1, and CCL5.⁵⁰⁾ The various subsets of TAMs can be primarily classified into two categories: M1- and M2-polarized macrophages. M1-polarized macrophages exhibit a pro-inflammatory phenotype that promotes Th1 responses and kills tumor cells. In contrast, M2-polarized macrophages display an immunosuppressive effect that enhances tumor growth by promoting Th2 responses. In comparison to the TME of EBV-negative tumors, the TME of EBV-positive tumors is distinguished by a more pronounced infiltration of TAMs.^51–55) Also, M2-TAMs have been identified as contributors to the advancement of numerous EBV-associated tumors.^28,56,57)

DCs serve as immune cells that capture and process antigens, subsequently presenting them to T cells. The activation and maturation of DCs into diverse functional subsets is primarily dependent on the cytokine milieu within the TME. The infiltration of DCs into the TME has been observed in several EBV-associated tumors.^58–60) Furthermore, a greater number of DCs are present in the TME of EBV-positive GC than in EBV-negative GC.⁶¹⁾ Additionally, mature DCs are situated in close proximity to tumor cells,⁶²⁾ indicating a functional interconnection between the two cell types that collectively shape the tumor immune microenvironment.

2.1.2.3. NK Cells

NK cells play a pivotal role in the regulation of antitumor immune responses. However, they are detected in a lower proportion than other tumor-infiltrating immune cells in the stroma of EBV-associated tumors.⁶³⁾ In EBV-positive HL, the proportion of NK cells is notably greater compared with EBV-negative HL,⁶⁴⁾ which is linked to the activation of the tumor-specific immune response.^65,66)

2.1.2.4. B Cells

As the natural host cells of EBV, B cells are present in EBV-associated tumors, albeit in lesser numbers than T cells. They are predominantly located within the tumor stroma.⁶⁷⁾ EBV infects B cells, prompting their maturation into plasma cells. These cells subsequently secrete copious quantities of antibodies, which stimulate other immune cells, including T cells.

2.1.2.5. Cancer-Associated Fibroblasts (CAFs)

CAFs derived from non-neoplastic fibroblasts interact with malignant cells within the TME, leading to the acquisition of aggressive characteristics that facilitate tumor progression. CAFs are responsible for the generation of ECM components, the production of growth factors and cytokines, the promotion of neovascularization, and the regulation of immune responses. CAFs synthesize and secrete collagen, fibronectin, and other matrix molecules, thereby forming a supportive structure around tumors. The ECM provides a supportive environment for tumor cell growth, invasion, and metastasis. Additionally, CAFs are capable of producing a variety of growth factors and cytokines, including tumor necrosis factor (TNF), TGF-β, and mesenchymal stem cell factor. These factors have been demonstrated to influence a number of key functions in tumor cells, like proliferation, survival, metastasis, and drug resistance. Moreover, CAFs facilitate the development of blood vessels around tumors by producing angiogenic factors, including vascular endothelial growth factor (VEGF) and other mediators. The process of angiogenesis provides tumors with the nutrients and oxygen needed for their dysregulated survival and growth. Moreover, CAFs influence tumor immunity by modulating the composition and quantity of infiltrating immune cells. Additionally, CAFs can impede immune cell attacks against tumor cells and assist tumor cells in evading immune surveillance by releasing immunosuppressive factors. It is noteworthy that CAFs promote tumor progression by secreting proteases that degrade the ECM, thereby facilitating regional invasion and distant metastasis.^68,69) CAFs are typically situated close to tumor cells. They are particularly evident in NPC, with varying degrees of prevalence, and are also present in EBV-positive GC.^70,71) It has been demonstrated that the CAFs present in EBV-infected tumors undergo remodeling as a result of LMP1-mediated modulation of the nuclear factor-kappaB (NF-κB) or extracellular signal-regulated kinase (ERK)–mitogen-activated protein kinase (MAPK) pathway.^72,73)

2.1.2.6. Endothelial Cells (ECs)

ECs, which line tumor blood vessels, are involved in the pathogenesis and progression of human cancers, including processes such as inflammation, fibrinolysis, and tumor angiogenesis.⁷⁴⁾ Tumor cell-released VEGF mobilizes ECs, which are crucial for the neoangiogenesis of EBV-positive tumors.^75,76) The small RNAs encoded by Epstein–Barr virus (EBERs) that are released from the cells infected with EBV alter the functional characteristics of ECs and enhance angiogenesis by increasing vascular cell adhesion molecule (VCAM)-1 expression.⁷⁷⁾ Moreover, EBV infection consistently boosts the growth of transplanted tumors and increases angiogenesis by raising VEGF production in NPC.⁷⁸⁾ Furthermore, the process of tumor angiogenesis is regulated by stromal interaction molecule 1 (STIM1)-dependent signaling, which controls the delivery of exosomal EBV-LMP1 to ECs in NPC.⁷⁹⁾

2.2. Molecular Components

Alongside cellular components, cytokines and chemokines also have an impact on the TME. The cytokines and chemokines emitted by multiple cells like B cells, DCs, and TAMs, oversee many functional activities of tumor and non-tumor cells in the EBV-reconfigured TME, thereby advancing disease progression.^80–82)

The remodeling of the TME is largely mediated by cytokines and chemokines, which induce proinflammatory, immunosuppressive, and chemotactic effects. IL-1β, a pro-inflammatory cytokine mainly released by monocytes and macrophages, can be activated by EBV genomic DNA and EBERs.⁸³⁾ IL-1β levels are elevated in EBV-positive GC.⁸⁴⁾ IFN-γ, mainly produced by NK cells, Th1 cells, and DCs, can be attracted by EBV-infected cells and has been shown to increase in EBV-positive GC.⁸⁴⁾ As a crucial cytokine for immune modulation, IFN-γ drives macrophages to differentiate into M1-polarized macrophages, which are pro-inflammatory, thereby creating an inflammatory TME.⁸⁵⁾ Moreover, the 10 kDa protein induced by IFN-γ, known as IP-10, is increased in tumors positive for EBV.⁸⁶⁾ IP-10, also referred to as CXCL10, belongs to the CXC chemokine family and is chiefly secreted by monocytes, macrophages, and endothelial cells, participating in chemotaxis. It promotes apoptosis, influences cell growth, and has angiostatic effects.⁸⁷⁾ Another member of the CXC chemokine family, CXCL12, is secreted by macrophages and CAFs and is also known as stromal cell-derived factor-1.^88–90) CXCL12 triggers pro-inflammatory and chemotactic responses and is increased in EBV-positive tumors.^90,91) Compared with EBV-negative tumors, EBV-positive tumors show elevated IL-10 levels, which are mainly secreted by T cells and DCs, resulting in an immunosuppressive effect.^92,93) In EBV-related tumors, there is a strong correlation between increased IL-10 levels and local immune suppression.⁹⁴⁾ Additionally, EBV-positive tumors exhibit an upregulation of other immunosuppressive cytokines such as IL-4, IL-6, and IL-13.^95–97) Table 1 illustrates the abundant molecular composition of the EBV-positive TME.

Table 1. Molecular Components of the Tumor Microenvironment

Type	Cell type of origin	Function in TME remodeling
Interleukins (ILs)
IL-1	Monocytes and macrophages	Promotes inflammation and angiogenesis
IL-6	Macrophages, T cells, and B cells	Promotes tumor cell proliferation, invasion, and anti-apoptotic ability, inhibits immune cell activity
IL-10	T cells and dendritic cells	Inhibits activation of immune cells and exerts immunosuppressive effects, which in turn, promote tumor cell growth
Chemokines
CCL2	Monocytes and macrophages	Recruits mononuclear and macrophage cells, promotes inflammatory response and tumor angiogenesis, and regulates immune response
CCL3 and CCL4	Macrophages and T cells	Regulates inflammation and cell migration
CCL5	T cells, monocytes, and macrophages	Promotes the inflammatory response and immune cell infiltration
CXCL10	Monocytes and macrophages	Recruits immune cells into the TME, induces apoptosis, regulates cell growth, and mediates angiostatic effects
CXCL12	Macrophages and CAFs	Induces pro-inflammatory and chemotaxis effects
TNF-α	Monocytes and macrophages	Promotes the inflammatory response, induces apoptosis, and promotes tumor angiogenesis
Other molecular components
IFN-γ	NK cells, Th1 cells, and dendritic cells	Mediates immune regulation by promoting macrophages to differentiate into M1-polarized macrophages
HIF-1α	N/A	Promotes tumor angiogenesis and regulates metabolic adaptation
VEGF	Tumor cells	Promotes angiogenesis
TGF-β	Tumor cells	Promotes EMT and angiogenesis, inhibits the immune response, and regulates matrix remodeling

TME, tumor microenvironment; CAF, cancer-associated fibroblast; NK, natural killer; EMT, epithelial–mesenchymal transition.

3. MECHANISMS BY WHICH EBV REMODELS THE TME

3.1. Immunosuppression and Immune Evasion

3.1.1. Recruitment and Polarization of Immune Cells

Persistent EBV infection modulates the composition of immune cells within the TME. EBV recruits immunosuppressive cells through the encoding and release of EBV products. For example, EBV has been observed to promote the recruitment of Treg cells and MDSCs, which have the potential to suppress T cell activation and interfere with antitumor immunity, thereby enabling tumor growth.^98,99) Treg cells accomplish this by suppressing the activation and proliferation of other immune cells, including T cells, B cells, and DCs. EBNA2 has been demonstrated to induce the production of IL-10, thereby stimulating the activity of regulatory T cells. EBNA1 upregulates the expression of the chemokine CCL20 in Reed–Sternberg cells, thereby promoting the migration of Treg cells in EBV-associated HL.¹⁰⁰⁾ Moreover, MDSCs, which are another type of immune cell that regulates the immune response and supports immune evasion in the TME, can also be activated by EBV-encoded molecules. Glycolysis mediated by LMP1 results in the clonal expansion of MDSCs in NPC.¹⁰¹⁾ Furthermore, the polarization of TAMs into the M2 phenotype, which supports tumor progression, is induced by EBV. This infection activates the ataxia telangiectasia and Rad-3-related (ATR) pathway, hastening the conversion of TAMs to the M2 phenotype in NPC.¹⁰²⁾ ATR is a pivotal kinase that plays a role in the single-stranded DNA damage response, which can be triggered by EBV in NPC.¹⁰²⁾ TNF-α and TGF-β, which regulate the polarization of M2-TAMs, might play a role in ATR. ATR, in turn, boosts the impact of TNF-α by triggering the downstream signaling molecule NF-κB. Conversely, ATR influences the polarization state of macrophages by modulating the phosphorylation status of mothers against decapentaplegic homolog (SMAD) proteins via the TGF-β signaling pathway. While TNF-α has been demonstrated to inhibit the polarization of macrophages to M2-TAMs by producing IL-13, this ultimately results in a reduction in the number of M2-TAMs.^103,104) TGF-β facilitates the polarization of macrophages into M2-TAMs, a process that is accompanied by the upregulation of IL-10 and the downregulation of TNF-α and IL-12.^105,106) Through the ATR pathway, EBV infection facilitates the shift of macrophages to M2-TAMs by boosting TGF-β and reducing TNF-α.¹⁰²⁾ The collective findings indicate that EBV infection establishes an immunosuppressive TME to facilitate tumor progression.

3.1.2. Establishment of a Tumor Immune Escape Microenvironment

A dense presence of lymphocytes is a typical pathological trait of tumors linked to EBV. The presence of both tumor-infiltrating lymphocytes and EBV-infected tumor cells indicates a potential immune evasion mechanism within the TME.

T cells are capable of recognizing and responding to tumor-expressed antigens, which play a pivotal role in antitumor immunity. However, in the case of chronic and persistent EBV infection, the state of T cell differentiation and development transforms, resulting in a state of T cell exhaustion. EBV employs a range of strategies to evade host immune responses. Initially, EBV can hinder cytotoxic T lymphocytes (CTLs) from identifying and destroying infected cells by decreasing the expression level of major histocompatibility complex (MHC) class I HLA genes.¹⁰⁷⁾ Secondly, EBV encodes a series of viral signaling products that contribute to the establishment of the tumor immune escape microenvironment by inhibiting immune checkpoint surveillance. Programmed death-ligand 1 (PD-L1), which is expressed on the surface of tumor cells, binds to programmed death protein 1 (PD-1), an inhibitory receptor that is present on the surface of T cells. This binding inhibits the activation of T cells and prevents them from attacking tumor cells, thereby enabling tumor cells to evade the immune system. LMP1, a primary gene product of EBV, has been demonstrated to stimulate the expression of PD-L1 through a variety of signaling pathways, including Janus kinase (JAK)/signal transducer and activator of transcription (STAT), AP-1, and NF-κB pathways.^108,109) EBNA1 activates the JAK2/STAT1/IRF-1 signaling pathway, which in turn induces PD-L1 expression.¹¹⁰⁾ EBNA2 enhances PD-L1 expression by suppressing miR-34a via the reduction of early B-cell factor 1.¹¹¹⁾ Moreover, circBART2.2 enhances PD-L1 expression by interacting with the retinoic acid-inducible gene I (RIG-I) protein and triggering the RIG-I pathway in NPC.¹¹²⁾ Additionally, the expression of PD-L1 is increased by EBV-miR-BART11 and miR-BART17-3p through their targeting of the transcriptional repressors forkhead box P1 and polybromo 1 in both EBV-associated NPC and GC.¹¹³⁾ In addition to PD-1, other surface inhibitory receptors (IRs), such as lymphocyte activation gene 3 (LAG3), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), T-cell immunoreceptor with immunoglobulin (Ig) and ITIM domains (TIGIT), and T-cell Ig and mucin domain-containing protein 3 (TIM3), are elevated in the TILs of EBV-related malignancies.²⁴⁾ Notably, the consistent upregulation of multiple IRs is a distinctive characteristic of T-cell exhaustion.^114,115) All IRs are expressed at high levels in NK/T-cell lymphoma, an aggressive T-cell lymphoma with a strong correlation to EBV infection, which, in turn, results in an immunosuppressive TME.¹¹⁶⁾

3.2. Promotion of Angiogenesis and Vasculogenic Mimicry

Blood vessels within tumors are crucial parts of the TME. EBV encourages the creation of new blood vessels to aid tumor expansion, a process called tumor angiogenesis. EBV enhances angiogenesis by triggering angiogenic factors like VEGF,^117,118) basic fibroblast growth factor,^119,120) and interleukin-8.^121,122) Moreover, EBV activates a number of signaling pathways that are implicated in tumor angiogenesis, including the NF-κB, JAK/STAT, and MAPK/ERK pathways. Activation of these pathways results in elevated expression levels of angiogenic factors and enhanced endothelial cell migration and proliferation. To illustrate, LMP1 stimulates VEGF expression via the JAK/STAT and MAPK/ERK signaling pathways.¹¹⁷⁾ Moreover, EBV infection enhances the stability of hypoxia-inducible factors, especially hypoxia inducible factor (HIF)-1α, which in turn promotes VEGF expression.¹²³⁾

In addition to VEGF-mediated angiogenesis, a novel tumor vasculature-forming pattern, termed vasculogenic mimicry (VM), has been observed. This phenomenon refers to the formation of vascular channels comprising tumor cells instead of endothelial cells. These channels provide a blood supply, which maintains unregulated tumor proliferation. In EBV-related epithelial tumors, LMP2A enhances VM through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/HIF-1α pathway,¹²⁴⁾ while LMP1 enhances VM via VEGFA/VEGFR1 signaling in NPC.¹²⁵⁾ Moreover, the expression of CXCL8, which is upregulated by EBV, is promoted by the NF-κB signaling pathway, which in turn facilitates the formation of VM in EBV-associated GC.¹²⁶⁾ Furthermore, EBV-miR-BART1-5p enhances VM and angiogenesis by controlling VEGF and activating the PI3K/Akt/mTOR/HIF1-α pathway, relying on Spry2 in NPC.¹²⁷⁾

3.3. Induction of Epithelial–Mesenchymal Transition (EMT)

The EMT process is typically distinguished by a reduction in cell–cell adhesion, which enables the migration and invasive behavior of epithelium-derived cells.¹²⁸⁾ EBV has been demonstrated to promote EMT, thereby enabling epithelial tumor cells to acquire a more aggressive mesenchymal phenotype. A number of transcription factors, including Snail, Slug, Twist, β-catenin, Zeb1, and Zeb2,¹²⁹⁾ have been shown to contribute to EMT by binding to the E-cadherin promoter and inhibiting its transcriptional activity.¹³⁰⁾ Both EBV-encoded proteins, such as LMP1, LMP2A, and EBNAs, as well as EBV-miRNAs, are involved in the promotion of EMT.^131–135) The microRNA EBV-miR-BART7-3p regulates the PI3K/Akt/GSK-3β signaling pathway by targeting the phosphatase and tensin homolog (PTEN). A reduction in PTEN expression levels has been observed to result in elevated levels of Snail and β-catenin expression.¹³²⁾ In NPC cells, EMT is facilitated by EEBV-miR-BART10-3p through its targeting of BTRC and regulation of downstream substrates, β-catenin and Snail.¹³³⁾ EBV-miR-BART8-3p triggers EMT by directly affecting RNF38 through the NF-κB and Erk1/2 signaling pathways in NPC.¹³⁴⁾ EBV-miRNA-BART12 suppresses tubulin polymerization promoting protein 1, which results in the inhibition of α-tubulin acetylation through the promotion of microtubule assembly and cytoskeletal reorganization.¹³⁵⁾ The expression of the transcription factor Snail is regulated by EBV-miR-BART12, which also inhibits cell migration and proliferation in EBV-associated GC.¹³⁶⁾ It is noteworthy that EMT regulators, such as Snail, Twist, and ZEB, and EMT-related transcription factors, such as E-cadherin, N-cadherin, vimentin, and β-catenin, are markedly upregulated in tumor cells with VM, indicating that the EMT program also plays a role in VM.¹³⁷⁾ A schematic diagram of the pathway through which EBV remodels the functional phenotype of tumor and non-tumor cells in the EBV-positive TME is shown in Fig. 1.

Fig. 1. The Mechanisms by Which EBV Modulates the Functional Phenotype of Tumor and Non-tumor Cells within the Tumor Microenvironment (TME)

EBV infection promotes the differentiation of stem cells in the bone marrow into myeloid-derived suppressor cells (MDSCs) and increases the number of MDSCs in the TME. MDSCs facilitate the differentiation of naive CD4+ T cells into regulatory T (Treg) cells and the transdifferentiation of Th17 cells into Treg cells by secreting retinoic acid and TGF-β. MDSCs induce immunosuppressive activities in Treg cells by regulating the release of IL-10 and IFN-γ. Furthermore, MDSCs facilitate the M2 polarization of tumor-associated macrophages (TAMs) by secreting IL-10 and TGF-β. EBV-infected cells release pro-inflammatory factors, including IL-6, IL-1β, and TNF-α, which attract endothelial cells (ECs) and initiate an inflammatory response. Vascular endothelial growth factor (VEGF) is secreted by EBV-infected cells, stimulating the proliferation of endothelial cells and promoting angiogenesis. Furthermore, EBV-infected cells facilitate the M2-type polarization of TAMs by secreting IL-10 and TGF-β. Infection with the Epstein–Barr virus (EBV) activates fibroblasts and promotes their transformation into tumor-associated fibroblasts (TAFs) by releasing interleukin-6 (IL-6), IL-1β, and transforming growth factor-β (TGF-β). EBV-encoded latent membrane protein 1 (LMP1) has been demonstrated to promote the production of TAFs by activating the NF-κB and MAPK signaling pathways. LMP1 has been demonstrated to facilitate the M2-type polarization of TAMs by activating the TLR signaling pathways. Furthermore, several EBV-encoded products, including LMP1, EBNA1, and microRNAs, have been shown to upregulate PD-L1 expression on tumor cells, leading to T-cell exhaustion.

3.4. Modulation of Cytokines and Chemokines

EBV infection dysregulates the production of various cytokines and chemokines in the TME. NF-κB and STAT3 are two crucial signaling axes that play a pivotal role in TME remodeling. EBV-LMP1 has been demonstrated to induce the expression of a multitude of cytokines, chemokines, and other signaling molecules through the activation of NF-κB, STAT3, and other pathways. All of these signaling pathways are implicated in tumor immune evasion, angiogenesis, invasion and metastasis, and EMT, as previously discussed in the context of EBV-associated tumors.^138–141)

Additionally, EBV modifies the composition of the ECM within the TME. This facilitates invasion and metastasis by inducing the expression of matrix metalloproteinases (MMPs), which degrade and remodel the ECMs.^142,143) Furthermore, EBV stimulates the synthesis of fibronectin and other ECM proteins, which serve to further modulate the TME and facilitate tumor progression.¹⁴³⁾ Together, these cytokines and chemokines aid in remodeling and create favorable local conditions for tumor growth, progression, and therapy resistance in EBV-related tumors.

4. THERAPY FOR EBV-ASSOCIATED TUMORS

4.1. Immune Checkpoint Inhibitors

The restoration of exhausted T cells represents a promising strategy for the treatment of cancer. The results have been promising, and the approach is regarded as a significant advance in cancer immunotherapy. Immune checkpoint inhibitors facilitate the recognition and destruction of cancer cells by inhibiting checkpoint proteins in immune cells. The aforementioned checkpoint proteins include PD-1, CTLA4, TIM3, TIGIT, and LAG3. These inhibitory effects result in the suppression of T cell activation and the promotion of T cell exhaustion. It is postulated that immune checkpoint inhibitors have the potential to convert exhausted T cells, thereby restoring EBV-specific cytotoxic effects against malignant cells.

A number of immunotherapeutic agents, including PD-1 and PD-L1 inhibitors such as pembrolizumab, nivolumab, atezolizumab, and durvalumab, as well as CTLA-4 inhibitors such as ipilimumab and tremelimumab, are currently being evaluated for their efficacy in treating EBV-associated tumors. Some of these agents have demonstrated promising results in this regard.^144,145) For example, pembrolizumab and nivolumab have demonstrated efficacy in the treatment of EBV-associated B-cell lymphoma and NPC.^146–148) Immune checkpoint inhibitors have demonstrated efficacy as first-line therapies for recurrent and/or metastatic NPC when combined with chemotherapy.¹⁴⁶⁾ Nevertheless, the rationale behind the lack of notable efficacy of anti-PD-1 monotherapy and the viability of combining multiple immune checkpoint inhibitors remain to be elucidated.

4.2. T Cell Therapy

4.2.1. EBV-Specific Cytotoxic T Lymphocyte Therapy

Several clinical trials have demonstrated the efficacy of EBV-specific CTL therapy for treating EBV-associated tumors, particularly NPC.^149,150) The in vitro detection of EBV-specific CTLs has the potential to enhance the immune response to LMP2, thereby facilitating more effective treatment of patients with NPC.¹⁴⁹⁾ Moreover, a clinical trial has demonstrated that the combination of chemotherapy and EBV-specific CTL therapy is an effective approach for the treatment of NPC.¹⁵⁰⁾

4.2.2. T-Cell-Receptor-Engineered T-Cell Therapy

T cells that have been genetically modified to express receptors that are specific to tumor-associated antigens are referred to as T-cell-receptor-engineered T (TCR-T) cells. TCR-T cells demonstrate considerable promise for the treatment of EBV-associated tumors.¹⁵¹⁾ TCR-T cells can be genetically engineered to target LMP1, LMP2, and EBNA1 in NPC.¹⁵²⁾ It has been shown that LMP2-expressing xenografts are inhibited by LMP1- or LMP2-specific TCR-T cells in murine models.^151,152)

4.3. Inhibition of VM

A growing body of evidence suggests that tumor growth and metastasis in EBV-associated tumors are closely associated with angiogenesis. At present, anti-angiogenic therapy represents an efficacious strategy for the treatment of EBV-associated tumors. For instance, in nasopharyngeal carcinoma, although angiogenic drugs have demonstrated encouraging outcomes in EBV-associated tumors, they have only resulted in a slight improvement in overall survival.¹⁵³⁾ The recurrence and metastasis of EBV-related tumors have not demonstrated a significant improvement. This indicates the potential existence of an alternative blood supply, such as VM, which may facilitate the growth of EBV-associated tumors despite the inhibition of classical angiogenesis. Consequently, VM inhibition may represent an efficacious therapeutic strategy to enhance the efficacy of anti-angiogenic treatments for EBV-associated tumors. Targeting tumor-cell-derived exosome-enveloped EBV-miR-BART1-5p-antagomiRs has been demonstrated to exhibit both anti-VM and anti-angiogenic effects via a Spry2-dependent mechanism in NPC.¹²⁷⁾

4.4. Deconstruction of the Tumor Immunosuppressive Microenvironment (TIME)

The TIME poses a significant challenge in cancer immunotherapy. A successful treatment approach involves dismantling the TIME by preventing the recruitment of Treg cells and MDSCs and stopping TAMs from polarizing to the M2 phenotype. Also, inhibitors of cytokines and growth factors, combined with ECM-targeting therapies that inhibit MMPs and other ECM-modulating factors, might be effective therapeutic approaches for treating tumors associated with EBV.

5. SUMMARY

Persistent EBV infection plays a direct remodeling role in the TME, thereby enabling EBV-associated tumors to become more aggressive. EBV and its products regulate the expression level of various cytokines, chemokines, and growth factors via a variety of signaling pathways, such as the NF-κB and STAT3 pathways, thereby modulating the composition of the TME. EBV plays a role in the polarization of TAMs to the M2 phenotype and in the recruitment of Treg cells and MDSCs, which together contribute to the formation of a distinctive tumor immune microenvironment. EBV downregulates the expression of MHC class I HLA genes, thus suppressing the recognition and clearance of EBV-infected cells by CTLs. Receptor ligands, such as PD-L1, are upregulated by EBV-encoded products, which in turn inhibit T cell activation, thus creating a TIME. Additionally, EBV has been demonstrated to facilitate tumor angiogenesis and VM through the NF-κB, JAK/STAT, and MAPK/ERK pathways. Furthermore, EBV alters the composition of the ECM by stimulating the expression of MMPs and other ECM proteins. Immune checkpoint inhibitors, such as pembrolizumab and nivolumab, have demonstrated efficacy in the treatment of EBV-relevant cancers. Additionally, T-cell therapies, including EBV-specific CTLs and TCR-T therapies, have shown promising results in the treatment of EBV-associated tumors¹⁵⁴⁾ (Fig. 2).

Fig. 2. Innovations in the Treatment of EBV-Associated Tumors

(a) T cells engineered with LMP1-specific receptors (CAR-T/TCR-T) are expanded ex vivo and infused into patients with EBV-associated malignancies. (b) Anti-PD-1/PD-L1 antibodies are applied to block the signaling pathways that suppress tumor immunity and restore T cell function. (c) Vaccines are designed to deliver EBV antigens to dendritic cells, leading to antigen cross-presentation via MHC-I, which activates cytotoxic CD8⁺ T cells and induces tumor-specific immunity.

Acknowledgments

This study was supported by the National Natural Science Foundation of China (82002859), the Guangxi Natural Science Foundation (2023GXNSFAA026179), the First-Class Discipline Innovation-Driven Talent Program of Guangxi Medical University awarded to J. Zhang, the Key Talent Program of Guangxi Zhuang Autonomous Region (Bagui Young Excellence Talents) granted to J. Wei, and the Guangxi Medical and Health Key Discipline Construction Project.

Conflict of Interest

The authors declare no conflict of interest.

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