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Unveiling immune resistance mechanisms in nasopharyngeal carcinoma and emerging targets for antitumor immune response: tertiary lymphoid structures

Journal of Translational Medicine volume 23, Article number: 38 (2025) Cite this article

Abstract

Nasopharyngeal carcinoma (NPC) is a prevalent malignancy in China, commonly associated with undifferentiated cell types and Epstein-Barr virus (EBV) infection. The presence of intense lymphocytic infiltration and elevated expression of programmed cell death ligand 1(PD-L1) in NPC highlights its potential for immunotherapy, yet current treatment outcomes remain suboptimal. In this review, we explore the tumor microenvironment of NPC to better understand the mechanisms of resistance to immunotherapy, evaluate current therapeutic strategies, and pinpoint emerging targets, such as tertiary lymphoid structures (TLSs), that could enhance treatment outcomes and prognostic accuracy. TLSs have demonstrated positive prognostic value in NPC, making them a promising target for future therapies. This review summarizes the key characteristics of TLSs and latest research in the context of NPC. We are optimistic that targeting TLSs could improve immunotherapy outcomes for NPC patients, ultimately leading to more effective treatment strategies and better patient survival.

Introduction

Nasopharyngeal carcinoma (NPC) originates from the nasopharyngeal mucosal layer, and is categorized into keratinized, non-keratinized, and basal-like. It is notably prevalent in Asia, with the non-keratinized variant being significantly associated with Epstein-Barr virus (EBV) infection [1]. Although NPC demonstrates sensitivity to radiotherapy, late-stage diagnosis and absence of early detection biomarkers lead to suboptimal outcomes, which are further compounded by treatment complications [1, 2]. The standard treatment for NPC typically involves chemoradiotherapy [3], but relapse rates remain high. Platinum-based chemotherapy remains the conventional approach, underscoring the need to identify patients who are most likely to respond favorably [4].

With the advancements in tumor research, immunotherapy has gained prominence and has sparked significant interest in its application to NPC. Current immunotherapy strategies for NPC include active immunotherapy, adoptive immunotherapy, and immune checkpoint inhibitors. Regarding active immunotherapy, EBV infection is a known contributor to cancer development, making it a promising therapeutic target. Research is currently focused on preventive vaccines against EBV to reduce the incidence of EBV-related diseases by limiting viral infection. Vaccine targets include EBV glycoproteins gp350, gH/gL, gB, gp42 serve as vaccine targets [5]. Additionally, EBV cancer proteins like EBNA and LMP are being explored as targets to eradicate latent infection within the host [6]. Moreover, injection of EBV-associated antigens or dendritic cells (DCs) capable of presenting these antigens (antigen-presenting cells, APCs) has shown potential in amplifying EBV antigen-specific CD8+T cells [7]. Adoptive immunotherapy involves the ex vivo culture of autologous CD8+T cells, which were then reintroduced into the body to target EBV-specific antigens such as Epstein-barr virus nuclear antigen (EBNA) and Latent membrane protein (LMP). Studies have demonstrated that this immune response to EBV can produces long-lasting anti-tumor effects [8]. Additionally, adoptive immunotherapy is associated with fewer adverse effects compared to conventional therapies [9]. Immune checkpoint inhibitors (ICIs) work by restoring the immune activity of immune cells, and countering the immunosuppression induced by tumor cells [10].

Major immune checkpoints, such as cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and PD-L1, inhibit lymphocytes activity, allowing immune cells to evade immune detection. In NPC, PD-L1 expression is prevalent and associated with a poor prognosis. Anti-PD1/PDL-1 therapies have shown promising results in clinical trials, significantly prolonging survival in patients with recurrent/metastatic platinum-refractory NPC. However, resistance to PD-1/PD-L1 inhibitors may develop through T cell dysfunction and decreased immunogenicity [10].

Face with the challenges of NPC immunotherapy, we conducted annalysis to understand the causes of resistance. In our exploration of potential new target for NPC immunotherapy, we identified TLSs, which may offer a novel approach for improving immunotherapy outcomes. Typically absent under physiological conditions, TLSs are frequently found in chronically inflamed environment. Mature TLSs characterized by the presence of T cells (CD 4 + T follicular helper cells), B cells and follicular dendritic cells (FDCs). scattered macrophages, stromal cells [11], and high endothelial venules (HEVs) at the periphery [12]. TLSs, organized aggregate of immune cells in non-lymphoid tissues, have been identified in the pathological sections of some NPC patients and have been correlated with improved prognosis [13].

The resistance mechanism of immunotherapy

The emergence of drug resistance presents a significant challenge in the treatment of recurrent NPC [14]. The TME comprises a diverse range of cellular components, including infiltrating immune cells, cancer-associated fibroblasts (CAFs), endothelial cells, pericytes, and various non-cellular elements. Within the TME, there is a delicate balance between immunostimulatory and immunosuppressive factors [15].Upon the death of tumor cells, antigens are released, captured, and presented by antigen-presenting cells (APCs), which trigger the activation of T cells. These activated T cells then migrate to the tumor site, infiltrate and identify tumor cells, leading to their elimination. This initiates an immune cycle within the TME [15]. During the anti-tumor immune response, TLSs form, and the appearance of germinal centers signals their maturation. Plasma cells, derived from B cell differentiation, produce antibodies that induce apoptosis in tumor cells. The formation of antigen-antibody complexes enhances dendritic cell-mediated antigen presentation and reinforces memory cell responses, thereby amplifying the tumor immune cycle [16](Fig. 1). Despite the considerable potential of immunotherapy in NPCs, current clinical outcomes remain suboptimal [17,18,19]. The possible mechanisms underlying immunotherapy resistance in NPC are summarized in Table 1.

Fig. 1
figure 1

Tumor-immune circulation. The main process of tumor immunity is that dying cells release tumor cell antigens, and APCs initiate and activate T cells through antigen presentation. Activated T cells and other immune related cells are transported to the tumor site and infiltrate to recognize tumor cells, ultimately killing the tumor cells. The immune cycle process that forms the microenvironment. During the anti-tumor immune process, TLSs are formed, and the formation of germinal centers marks the maturation of TLSs, which play an effective anti-tumor response. B cells differentiate into plasma cells and secrete antibodies to promote tumor apoptosis. The formed antigen antibody complexes can amplify the antigen presentation effect of APCs, enhance memory of B cell responses, and ultimately amplify the immune cycle within the tumor

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Table 1 Mechanism of drug resistance in NPC
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Resistance related to EBV infection is particularly important. As a microbial component in the TME, EBV significantly influences tumor growth, invasion, and metastasis [20]. Compared to EBV-negative NPC, EBV-positive cases exhibit a stronger immunosuppressive microenvironment [21], facilitating immune evasion and tumor progression. EBV predominantly adopts type II latency, expressing proteins such as EBNA1, LMP1/2 (late membrane proteins), and EBER (small RNA encoded by EBV) [1]. EBNA1 downregulates P53, leading to gene mutations in cancer cells [22]. In advanced tumors, TGF-β1 promotes the chemotactic migration of regulatory T cells (Tregs) via the CXCL12-CXCR4 axis, reshaping the NPC microenvironment [23]. LMP1 stimulates epidermal growth factor receptor (EGFR), inhibits epithelial differentiation, and promotes cell cycle progression, thereby enhancing cell growth. Additionally, LMP1 activates NF-κB by binding to tumor necrosis factor (TNF) receptor-associated factor (TRAF), amplifying the immune response of lymphocytes and inhibiting DNA repair through the PI3K/Akt pathway [24]. TGF-βfurther suppresses the immune response while enhancing proliferation signals [25]. LMP2A promotes tumor transformation through activation of the Ras/PI3K/Akt and β-catenin/Wnt pathways [26]. LMP1 also activates the classic RAF/MEK/ERK pathway upon binding to receptors such as EGFR, FGFR, and VEGFR, inducing epithelial to mesenchymal transition (EMT) and increasing cell motility and invasiveness [27]. The JAK/STAT3 pathway inhibits apoptosis, promotes cell proliferation, and facilitates angiogenesis, thereby enhancing NPC’s invasive capabilities [28]. We have summarized and illustrated the pathway of immunosuppression induced by EBV-positive tumor cells in Fig. 2 [22,23,24,25,26,27,28].

Fig. 2
figure 2

Immunoresistance mechanisms related pathways in EBV + NPC. The interaction between the Epstein-Barr virus (EBV) glycoprotein BMRF-2 or gH/gL and integrins on epithelial cells alters the conformation of gH/gL and gB, leading to the fusion of the EBV envelope with epithelial cells. Ultimately, EBV is delivered into the cells. EBV commonly adopts type II latency, expressing like EBNA1, LMP1/2, and EBER. These oncoproteins manipulate various cellular pathways (such as P53, TGF-β1, EGFR, NF-κB, PI3K/Akt, RAF/MEK/ERK, JAK/STAT3), promoting tumor proliferation, survival, invasion

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Recent advancements in oncology underscore the crucial role of TME, particularly in immune modulation [29, 30]. Immune cells infiltration correlates with favorable prognoses, with the T cells, B cells, and stromal cells increasingly recognized for their influence on therapeutic responses [31, 32]. Despite the promise of immunotherapy, resistance remains a significant challenge, particularly in NPC [17, 33]. The expression of PD-L1 in EBV-associated NPC suggests PD-1/PD-L1 inhibitors may serve as effective therapies, with varied prognostic implications [34,35,36]. Understanding the TME, including TLSs, offers valuable insights into potentialimmunotherapy targets for NPC.

TLSs as the targets for antitumor immune response

Effective induction of an anti-tumor immune response within the TME is crucial for inhibiting tumor progression. However, despite a similar composition of infiltrating immune cell in certain tumors, patients exhibit varying prognosis, suggesting that interactions between immune cells and tumors extend mere presence. TLSs have emerged as significant factors to the anti-tumor immune response in NPC and hold considerable promise for immunotherapy [37].

Composition of TLSs

Histopathological analysis of NPC reveals extensive infiltration of immune cells surrounding and within tumor lesion [31], indicating a complex TME. Various methods for detecting TLSs are outlined in Table 2. The composition of TLSs varies across in different tumors [38]. For example, TLSs in non-small cell lung cancer primarily contains DC-LAMP + DCs [39], while TFH cells are common in TLSs associated with breast cancer [11]. In NPC, studies have identified a combination of markers of TLSs components, including germinal center B cell components, follicle-assisted CD4 + T cells, CXCL13 + CD8 + T cells, CXCL13 + fibroblasts. This leads us to consider whether the differences in TLSs components across various tumors may be a factor contributing to the variability in prognostic outcomes associated with TLSs.

Table 2 The advantages and features of TLSs observation methods
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The function of TLSs

The function of TLSs varies among different tumor types, which may be attributed to differences in TLSs differentiation, spatial location and overall function [37, 40]. Although consistent evaluation criteria for TLSs are lacking, it is widely accepted that the maturity of TLSs significantly influences their functionality [1]. The germinal center within TLSs plays a crucial role in tumor prognosis and has emerged as an independent prognostic marker in numerous solid tumors [41]. In tumor immunotherapy, an increasing number of studies have highlighted the important role of B cells in tumor immunity [42]. In immature TLSs, B cells may acquire immunosuppressive activity, however, in mature germinal centers, B cells undergo processes such as antibody class switching and somatic hypermutation to differentiate into mature plasma cells, thereby promoting anti-tumor immune responses [43]. Research has shown that infiltrated B cells were closely associated with TLSs [44]. Both infiltrating B cells and/or TLSs are considered valuable prognostic or predictive biomarkers [45].

Studies analyzing gene expression differences between normal nasopharyngeal tissue and NPC tissue have identified a close association between tumor-infiltrating B cells and NPC. The infiltration of B cells in NPC tissues was significantly higher than that in adjacent tissues, with specific B cell marker genes, such as CD79B and CD19, positively correlating with favorable prognosis in NPC [44]. However, not all B cell subsets are linked to positive outcomes in NPC. Some subsets expressing activation-related genes, as well as high-level transcription factor key genes (e.g., JUN, JUNB, FOS, and FOSB), which play critical roles in the immune microenvironment of NPC, are associated with better prognoses and may serve as potential targets for clinical immunotherapy. In contrast, subsets expressing proliferation-related genes (e.g., MKI67, TOP2A) exhibit poorer prognoses and fewer TLSs formations [44]. Cancer-associated fibroblasts (CAFs) can promote B cell aggregation and communication through secretion of CXCL13 and MIF signaling, respectively [46]. In NPC, often associated with viral infections such as Epstein-Barr virus (EBV), a significant positive correlation exists between EBV infection-specific genes (including genes specific to EBV infected cells and LMP1-related gene signatures) and TLSs characteristics [44]. EBV-positive patients tend to display higher levels of TLSs compared to EBV-negative patients, correlating with a better therapeutic response and overall prognosis. In other virus-associated cancers like EBV-positive gastric cancer [47] and human papillomavirus(HPV)-positive head and neck squamous cell carcinoma (HNSCC) [48], viral infections influence the composition of the TME, thereby affecting the formation of TLSs. For instance, EBV alters immune infiltration characteristics in gastric cancer tissues, while SEMA4A, a membrane-bound glycoprotein, plays a central role in the formation of immune aggregates in HPV-positive HNSCC [48].

The therapeutic potential of TLSs in NPC

The presence of TLSs within the TME of NPC has emerged as a significant factor influencing anti-tumor immune responses and patient outcomes. TLSs are organized aggregates of immune cells formed in non-lymphoid tissues and play a crucial role in promoting anti-tumor immunity. Therefore, inducing the formation of TLSs is a particularly promising immunotherapy. Research has identified several factors associated with the formation and function of TLSs in NPC (Fig. 3).

Fig. 3
figure 3

The therapeutic potential of TLSs in NPC. A. Modulating the immune cells-induced TLSs formation: The subsets CD4 + Th-CXCL13PD1 + CXCR5-cells in NPC can promote TLSs formation; B. Nano-vaccine injection-induced TLSs formation: The nano-vaccine activated the LT-α and LT-β pathways, and subsequently enhanced the expression of downstream chemokines CCL19/CCL21, CXCL10 and CXCL13 in the tumor microenvironment to promote the formation of TLSs; C. Chemotherapy-induced TLSs formation: GP chemotherapy induces ILB(innate-like B cell) through toll-like receptor 9 signaling. ILB further amplifies follicular helper cells and helper type 1 T cells via the ICOS-ICOS axis and subsequently enhances cytotoxic T cells in tertiary lymphoid organ-like structures with germinal center defects after chemotherapy; D. TLSs and ICB therapy are mutually beneficial

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TLSs associated immune cells

PD-1+CXCR5-CD4+TH-CXCL13 cells found in the TME of NPC samples play a critical role in recruiting tumor-associated B cells to participate in TLSs formation. These cells express the chemokine CXCL13, which attracts B cells, and secrete interleukin-21 (IL-21), promoting the differentiation of plasma cells and production of immunoglobulins. TGF-β and the transcription factor SOX-4 have been identified as key regulators of CXCL13 expression in these CD4 + TH cells. TLSs formed as a result significantly enhance the anti-tumor immune response and improve patient survival [13].

TLSs related nano-vaccines

In NPC mouse models, injecting a nano-vaccine composed of EBV’s EBNA1, combined with a bi-adjuvant of Mn2 + and cytosine-phosphate-guanine (CpG) formulated with tannic acid, has been shown to facilitate TLSs formation within tumors. This approach accelerates the anti-tumor response and inhibits tumor growth [49]. Nano-vaccines represent a promising avenue for future immunotherapy by inducing and accelerating TLSs formation in tumors.

Chemotherapy-induced TLSs formation

Gemcitabine combined with cisplatin (GP) chemotherapy is the standard treatment for nasopharyngeal carcinoma (NPC). Chemotherapy regimens such as GP, have been found to induce immune cell infiltration and form tertiary lymphoid organ (TLO)-like structures that may lack germinal centers. However, these GC-deficient TLOs may still hold clinical significance. In lung [43] and pancreatic [50] cancer patients who received neoadjuvant chemotherapy, an increase in immune cell composition suggested enhanced TLSs formation. These findings highlight the potential of chemotherapy in modulating the TME to enhance anti-tumor immunity [51], indicating that therapeutic interventions could reconstruct B cells to establish an effective anti-tumor response.

TLSs correlation with immune checkpoint blockade (ICB) therapy

The presence of TLSs has been significantly associated with improved responses to ICB therapy in various tumors. Studies have shown the emergence of TLSs following treatment with PD-1 or combined PD-1 and CTLA-4 blockade inhibitors [42]. The abundance of TLSs has been correlated with PD-L1 expression on immune cells [52]. Additionally, ICB therapy has been shown to enhance TLSs formation and function in many tumors, including melanoma and urothelial carcinoma [42]. By promoting TLSs formation, ICB therapy can further enhance its therapeutic efficacy [53]. Formation of TLSs was also found to be beneficial to the prognosis of patients in NPC [13].Therefore, inducing TLSs in NPC may improve the effectiveness of ICB treatment.

Summary and prospect

The TME plays a crucial role in the prognosis and treatment of NPC, particularly regarding immunotherapy. Understanding the complex interplay between tumor cells, immune cells, and the surrounding microenvironment is essential for developing effective immunotherapy strategies for NPC. Future research should focus on elucidating the mechanisms of treatment resistance and identifying novel targets within the tumor microenvironment. Given the challenges of immunotherapy resistance in NPC, studies have identified that TLSs as potential targets to enhance the treatment effect in patients. Investigating their formation, function, and correlation with treatment outcomes could provide valuable insights into optimizing immunotherapy approaches, including predicting treatment responses and exploring novel drugs targeting TLSs. Additionally, CXCL-13 shows promise as a novel target in NPC immunotherapy. Preliminary analyses suggest its association with favorable prognosis and its potential as a predictor of response to immune checkpoint blockade therapy in NPC. Further research is needed to elucidate its mechanisms of action and explore its therapeutic potential in combination with other targets, such as PD-L1. It is essential to recognize the unique features of NPC’s TME, including strong immune infiltration and high PD-L1 expression. Strategies for immunotherapy should be tailored to these specific characteristics rather than relying solely on conclusions drawn from other tumor types. Despite advancements in immunotherapy, resistance remains a significant challenge in NPC treatment. Continued research into novel targets and therapeutic approaches is crucial for overcoming resistance and improving patient outcomes.

In summary, further exploration of the TME, TLSs, CXCL-13, and other potential targets holds promise for advancing immunotherapy in NPC. By understanding the unique characteristics of NPC and developing targeted therapeutic strategies, we can enhance treatment efficacy and provide new hope for patients facing this challenging disease.

Data availability

Not applicable.

Abbreviations

NPC:

Nasopharyngeal carcinoma

EBV:

Epstein-barr virus

TLSs:

Tertiary lymphoid structures

TME:

Tumor microenvironment

CAF:

Cancer-associated fibroblast

DC:

Dendritic cell

APC:

Antigen-presenting cell

EBNA:

Epstein-barr virus nuclear antigen

LMP:

Latent membrane protein

ACT:

Adoptive cell therapy

MDSCs:

Myeloid-derived suppressor cells

ICIs:

Immune checkpoint inhibitors

CTLA-4:

Cytotoxic T lymphocyte-associated antigen-4

PD-L1:

Programmed cell death 1 ligand 1

TME:

Tumor microenvironment

TFH cell:

T follicular helper cell

FDCs:

Follicular dendritic cells

HEVs:

High endothelial venules

HPV:

Human Papillomavirus

HNSCC:

Head and Neck Squamous Cell Carcinoma

IL-21:

interleukin-21

CXCL-13:

C-X-C motif chemokine ligand 13

CCL21:

Chemokine (C-C motif) ligand 21

ICB:

Immune checkpoint blockade

PDAC:

Pancreatic ductal adenocarcinoma

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This work was supported by the National Nature Science Foundation of China (grant number: 81972838; 82272722; 82200019).

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Authors and Affiliations

  1. Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China

    Huilin Wang, Yuting Zhan, Jiadi Luo & Songqing Fan

  2. Hunan Clinical Medical Research Center for Cancer Pathogenic Genes Testing and Diagnosis, Changsha, Hunan, 410011, China

    Huilin Wang, Yuting Zhan, Jiadi Luo & Songqing Fan

  3. Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Weiyuan Wang

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SQF designed the research. HLW drafted the manuscript. YTZ and JDL improved the structure. SQF and WYW revised the manuscript. All authors read and approved the final manuscript.

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Wang, H., Zhan, Y., Luo, J. et al. Unveiling immune resistance mechanisms in nasopharyngeal carcinoma and emerging targets for antitumor immune response: tertiary lymphoid structures. J Transl Med 23, 38 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12967-024-05880-7

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Journal of Translational Medicine

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