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T cell fate regulation in EBV‑associated nasopharyngeal carcinoma (Review)

  • Authors:
    • Liuyang Zhang
    • Shun Ding
    • Dongzhui Chen
    • Benchi Cai
    • Zhonglin Mu
  • View Affiliations / Copyright

    Affiliations: Department of Otolaryngology, Head and Neck Surgery, The First Affiliated Hospital, Hainan Medical University, Haikou, Hainan 570102, P.R. China, Department of Pediatrics, First Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570102, P.R. China, Department of Neurology, Hainan General Hospital, Hainan Medical University, Haikou, Hainan 570311, P.R. China
    Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 106
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    Published online on: April 2, 2026
       https://doi.org/10.3892/or.2026.9111
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Abstract

Nasopharyngeal carcinoma, a malignancy associated with Epstein‑Barr virus, presents a complex immune editing landscape in which T cell fate determination carries out a central role. T cell metabolic exhaustion, Epstein‑Barr virus antigen presentation and tertiary lymphoid structure remodeling are important in the context of tumor immune evasion. Although individual mechanisms have been extensively studied, their interplay and collective contribution to immune editing remain incompletely understood. The present review summarizes the current advances in nasopharyngeal carcinoma immune editing, with a focus on the molecular network underlying T cell fate decisions. How these mechanisms can be leveraged to develop novel immunotherapeutic strategies is further discussed. By integrating recent findings, the present review aims to offer new insights into the intricate immune landscape of nasopharyngeal carcinoma and to provide a theoretical basis for improving immunotherapy efficacy.
View Figures

Figure 1

Schematic of defective antigen
processing and presentation mechanisms in NPC cells. In normal
cells, antigen processing occurs through the degradation of
endogenous proteins via the proteasome. The resulting peptides are
then transported to the ER, where they bind to MHC-I molecules and
are subsequently displayed on the cell surface. This process
ensures the recognition and clearance of abnormal cells by CD8+ T
cells, thereby achieving immune surveillance and elimination. By
contrast, in NPC cells, EBV latent infection leads to defects in
antigen presentation. The expression of EBV latent proteins impairs
the function of the TAP transporter, preventing efficient peptide
transport to the ER and thereby inhibiting MHC-I expression. These
defects reduce cross-presentation capacity, ultimately resulting in
the inability of T cells to recognize and activate NPC cells,
leading to immune evasion and promoting tumor progression. MHC-I,
major histocompatibility complex class I; TAP, transporter
associated with antigen processing; ER, endoplasmic reticulum; APC,
antigen-presenting cell; EBV, Epstein-Barr virus; NPC,
nasopharyngeal carcinoma; CD8+ T cell, CD8-positive T
lymphocyte.

Figure 2

Schematic of AICD in T cells in NPC.
EBV latent antigens are continuously presented by APCs, leading to
sustained activation and exhaustion of T cells. Chronic TCR
activation triggers immunosuppressive signals, resulting in T cell
dysfunction (T cell exhaustion) and reduced antitumor efficacy.
Activation of the PD-1/PD-L1 pathway, accumulation of ROS and
changes in mitochondrial membrane potential promote AICD. These
processes further enhance immune evasion by NPC cells, which
secrete immunosuppressive factors such as TGF-β and IL-10,
inhibiting T cell function and promoting tumor growth. EBV,
Epstein-Barr virus; APS, antigen-presenting cell; TCR, T cell
receptor; AICD, activation-induced cell death; PD-1/PD-L1,
programmed cell death protein 1/programmed cell death ligand 1;
ROS, reactive oxygen species; NPC, nasopharyngeal carcinoma.

Figure 3

Schematic of the epigenetic
regulatory network in the initiation and progression of T cell
exhaustion. T cells undergo distinct stages in response to
continuous antigen stimulation, including initial activation, early
depletion and late exhaustion, with accompanying epigenetic
regulatory changes. In the initial activation phase, T cells are
activated through TCR/CD28 and stimulated by APCs, leading to
chromatin opening and upregulation of transcription factors such as
Eomes and T-bet. Chronic stimulation thereafter drives T cells into
early depletion, characterized by increased expression of NR4A, TOX
and non-coding RNAs, along with DNA methylation and histone
modifications that result in the closure of functional gene loci.
Finally, during the late exhaustion stage, chromatin becomes
irreversibly locked, with increased H3K27me3, leading to a complete
loss of T cell killing function and contributing to tumor
progression and immune evasion. TCR, T cell receptor; CD28,
co-stimulatory receptor on T cells; APC, antigen-presenting cell;
Eomes, eomesodermin; T-bet, T-box transcription factor; H3K27ac,
acetylation of histone H3 on lysine 27; TOX, thymocyte
selection-associated high mobility group box; NR4A, nuclear
receptor subfamily 4 group A; LAG3, lymphocyte-activation gene 3;
PD-1, programmed cell death protein 1; HDAC, histone deacetylase;
me, methylation; Ac, acetylation; ZAP70, zeta-chain-associated
protein kinase 70; H3K27me3, trimethylation of histone H3 on lysine
27; NPC, nasopharyngeal carcinoma; Super enhancer, a cluster of
enhancers with the potential to drive gene expression at a high
level.

Figure 4

Schematic of the regulatory network
formed by TLSs in NPC. Following EBV infection, tumor-derived
cytokines activate dendritic cells, promoting the aggregation of B
cells and T cells, thereby enhancing local antitumor immunity.
During the progression of NPC, various immune cells (for example,
plasma cells, dendritic cells) and stromal cells (for example,
fibroblasts, endothelial cells) participate in the activation and
migration of CD4+ T cells by secreting chemokines such
as CXCL12 and CCL21. This process promotes the formation of HEVs
and the organization of germinal center-like structures, ultimately
improving prognosis or enhancing responses to immunotherapy. TLSs,
tertiary lymphoid structures; EBV, Epstein-Barr virus; NPC,
nasopharyngeal carcinoma; B/T cells, B lymphocytes and T
lymphocytes; CXCL12, C-X-C motif chemokine ligand 12; CCL21, C-C
motif chemokine ligand 21; HEVs, high endothelial venules;
CD4+ T, CD4-positive T lymphocyte.

Figure 5

Schematic diagram of the virological
mechanisms of immune evasion by EBV. After EBV infection of NPC
cells, immune evasion is achieved through multiple mechanisms that
suppress antitumor immune responses. The molecular mechanisms
include: i) Antigen presentation inhibition: EBV proteins (EBNA1,
BNLF2a and BCRF1) block the function of MHC class I molecules and
TAP transport, weakening the recognition capacity of
CD8+ T cells. ii) Anti-apoptosis and CTL evasion: BHRF1
and LMP1 inhibit apoptosis (for example, by blocking Bax) or
activate the NF-κB pathway, assisting tumor cells in evading
CTL-mediated killing. iii) Induction of T cell exhaustion: LMP1 and
BARTs mRNA upregulate the PD-L1/PD-1 signaling pathway, leading to
T cell dysfunction. iv) Remodeling of the TIME: Through the
secretion of factors such as IL-10, TGF-β and CCL20, EBV recruits
Tregs and MDSCs, further suppressing T cell activity and creating
an immunosuppressive microenvironment. EBV, Epstein-Barr virus;
NPC, nasopharyngeal carcinoma; EBNA1, Epstein-Barr nuclear antigen
1; BNLF2a, BamN-terminal latent protein family member 2a; BCRF1,
BamC-terminal reading frame 1; BHRF1, BamHI rightward reading frame
1; LMP1, latent membrane protein 1; BARTs, BamHI-A rightward
transcripts; MHC-I, major histocompatibility complex class I; TAP,
transporter associated with antigen processing; CTL, cytotoxic T
lymphocyte; PD-L1, programmed cell death ligand 1; PD-1, programmed
cell death protein 1; Treg cell, regulatory T cell; MDSCs,
myeloid-derived suppressor cells; CCL20, C-C motif chemokine ligand
20; TIME, tumor immune microenvironment.
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Zhang L, Ding S, Chen D, Cai B and Mu Z: T cell fate regulation in EBV‑associated nasopharyngeal carcinoma (Review). Oncol Rep 55: 106, 2026.
APA
Zhang, L., Ding, S., Chen, D., Cai, B., & Mu, Z. (2026). T cell fate regulation in EBV‑associated nasopharyngeal carcinoma (Review). Oncology Reports, 55, 106. https://doi.org/10.3892/or.2026.9111
MLA
Zhang, L., Ding, S., Chen, D., Cai, B., Mu, Z."T cell fate regulation in EBV‑associated nasopharyngeal carcinoma (Review)". Oncology Reports 55.6 (2026): 106.
Chicago
Zhang, L., Ding, S., Chen, D., Cai, B., Mu, Z."T cell fate regulation in EBV‑associated nasopharyngeal carcinoma (Review)". Oncology Reports 55, no. 6 (2026): 106. https://doi.org/10.3892/or.2026.9111
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Spandidos Publications style
Zhang L, Ding S, Chen D, Cai B and Mu Z: T cell fate regulation in EBV‑associated nasopharyngeal carcinoma (Review). Oncol Rep 55: 106, 2026.
APA
Zhang, L., Ding, S., Chen, D., Cai, B., & Mu, Z. (2026). T cell fate regulation in EBV‑associated nasopharyngeal carcinoma (Review). Oncology Reports, 55, 106. https://doi.org/10.3892/or.2026.9111
MLA
Zhang, L., Ding, S., Chen, D., Cai, B., Mu, Z."T cell fate regulation in EBV‑associated nasopharyngeal carcinoma (Review)". Oncology Reports 55.6 (2026): 106.
Chicago
Zhang, L., Ding, S., Chen, D., Cai, B., Mu, Z."T cell fate regulation in EBV‑associated nasopharyngeal carcinoma (Review)". Oncology Reports 55, no. 6 (2026): 106. https://doi.org/10.3892/or.2026.9111
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