Immune escape mechanisms and therapeutic advances in virus-associated hematological malignancies

Abstract

Virus-associated hematological malignancies have become a key focus in oncology research due to their complex pathological mechanisms and unique immune escape capabilities. In recent years, research in this area has increased with a deeper understanding of the role of viruses in tumorigenesis. However, the immune escape mechanisms in virus-associated hematological malignancies remain incompletely elucidated, posing challenges for the development and optimization of treatment strategies. This review summarizes the roles of various known viruses—particularly Epstein–Barr virus (EBV), human immunodeficiency virus (HIV), human T-cell leukemia virus type 1 (HTLV-1), Kaposi’s sarcoma-associated herpesvirus (KSHV), hepatitis B virus (HBV), and hepatitis C virus (HCV) in the pathogenesis of hematological malignancies. It focuses on elucidating how tumor cells utilize multiple immune escape mechanisms to evade host immune surveillance. Simultaneously, incorporating the latest research advances, it delves into cutting-edge therapeutic approaches, including targeting viral proteins, immune checkpoint inhibitors, chimeric antigen receptor T-cell (CAR-T) therapy, oncolytic viruses, virus-specific T-cell therapy (VST), and therapeutic vaccines. By integrating the molecular mechanisms of virus-associated hematological malignancies with clinical applications, this article aims to provide a theoretical basis and future research directions for precision therapy in this field.

Introduction

The critical role of viral infection in various hematological malignancies has gained widespread attention. Viruses such as EBV, KSHV, HTLV-1, HIV, HBV, and HCV have been confirmed to affect lymphocyte function through direct infection and induction of cell proliferation, leading to immune escape. This enables tumor cells to evade the body’s immune surveillance, thereby promoting tumor progression [1]. The interaction mechanisms between these viruses and hematological malignancies differ, with each virus associated with specific types of blood cancers, exhibiting unique infection mechanisms, pathogenesis, and clinical symptoms.

The development of virus-associated hematological malignancies is a complex, multi-stage, multi-factorial process. From viral infection and long-term latency to the eventual induction of tumor formation, the progression mechanisms involve the oncogenic effects of virus-encoded proteins, virus-mediated immune escape strategies, and dynamic remodeling of the tumor microenvironment (TME). In-depth investigation into how viruses escape host immune surveillance and modulate the microenvironment is crucial for elucidating viral carcinogenesis mechanisms and developing precision therapies. Currently, traditional chemotherapy faces efficacy bottlenecks due to difficulties in targeting virus-driven immune escape characteristics, necessitating novel therapies based on virus-microenvironment interaction mechanisms [2, 3]. This review aims to systematically analyze the molecular association network between viruses and hematological malignancies, explore cutting-edge therapeutic approaches such as targeting viral proteins, immune checkpoint inhibitors (ICIs), virus-specific T-cell therapy (VST), oncolytic viruses, CAR-T therapy, and therapeutic vaccines, to provide a theoretical basis for optimizing prognostic prediction tools and designing low-toxicity, high-efficiency combination treatment regimens.

Types of typical virus-associated hematological malignancies

Virus infection-associated lymphomas

Among hematological malignancies, several viruses (including EBV, HIV, HBV, and HCV) are associated with an increased risk of lymphoma. EBV is the most extensively studied virus in relation to lymphomas, particularly in extranodal NK/T-cell lymphoma (ENKTCL), Burkitt lymphoma (BL), and classical Hodgkin lymphoma (cHL) [4]. Studies show that EBV can infect B lymphocytes and establish latent infection, leading to tumor cell immune escape and thereby promoting tumor formation and development (Fig. 1); the degree of EBV infection is closely related to lymphoma prognosis, making monitoring its viral load clinically significant [5, 6]. As a key etiological factor in various B-cell lymphomas, EBV-encoded proteins play a central role in B-cell transformation and proliferation: Latent membrane protein 1 (LMP1) inhibits apoptosis and promotes B-cell proliferation and survival by activating the nuclear factor kappa B (NF-κB) and Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathways [7–10]. Epstein–Barr nuclear antigen 2 (EBNA2) drives malignant transformation and proliferation of B cells by hijacking the host transcriptional regulatory network (especially the NOTCH signaling pathway) and interacting with host transcription factors such as c-Myc [11–13].

Fig. 1. Typical virus-associated hematological malignancies with pathogenic mechanisms.

Epstein–Barr virus (EBV) infects B cells to establish latent infection, enabling immune escape and tumorigenesis (e.g., ENKTCL, BL, cHL); human immunodeficiency virus (HIV) impairs CD4⁺ T cell function, causing immune surveillance collapse that increases susceptibility to co-carcinogenic infections (e.g., EBV), elevating DLBCL/BL risks; hepatitis B virus (HBV) latently persists in lymphocytes/stem cells to disrupt immune responses and promotes malignant transformation (e.g., DLBCL) via miR-34a dysregulation and CREB-binding protein mutations/aberrant modifications; hepatitis C virus (HCV) utilizes NS3/4A proteins to dephosphorylate HuR, upregulating BCR signaling that drives B-cell proliferative disorders; human T-cell leukemia virus type 1 (HTLV-1) infects T cells to trigger viral integration, signaling pathway activation (e.g., NF-κB), and immunosuppression, culminating in ATLL; Kaposi’s sarcoma herpesvirus (KSHV/HHV-8) operates through latent (LANA-mediated genome maintenance/pro-survival signaling) and lytic cycles (promoting dissemination/inflammation) to cause MCD and PEL. This figure was created with BioRender.com.

HIV infection significantly increases lymphoma risk. The most common subtypes of HIV-associated non-Hodgkin lymphoma are HIV-associated diffuse large B-cell lymphoma (HIV⁺ DLBCL) and HIV-associated Burkitt lymphoma (HIV⁺ BL) [14]. HIV itself does not directly cause NHL, but due to impaired immune function in HIV-infected individuals, they are more susceptible to co-infection with other oncogenic viruses such as EBV [15]. HIV causes immune function collapse by destroying CD4⁺ T cells, preventing the immune system from effectively clearing cancerous cells (Fig. 1). Therefore, in the treatment of HIV-associated lymphomas, antiviral therapy is a critical component of the overall strategy, and these immune deficiencies must be considered.

Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), is a key causative agent of lymphoproliferative disorders such as primary effusion lymphoma (PEL) and KSHV-associated multicentric Castleman disease (MCD) [16]. After infecting the host, the virus can exist in both latent and lytic states, both contributing to pathogenesis. Latent infection is primarily maintained by the expression of the latency-associated nuclear antigen (LANA) protein, which not only facilitates viral genome persistence but also promotes malignant transformation of host cells. In the latent state, KSHV drives tumorigenesis by altering intracellular signal transduction pathways, particularly those related to cell proliferation and apoptosis [17]. Concurrently, KSHV lytic replication not only promotes viral spread but also induces inflammatory responses, further accelerating tumor development [18] (Fig. 1). Studies show that KSHV-infected tumor cells often exhibit significant immune evasion, a key component of its pathogenic mechanism [19]. In KSHV-associated malignancies like KS, PEL, and MCD, the virally encoded viral interleukin-6 (vIL-6) plays a central role. vIL-6 promotes cell proliferation and survival by mimicking host interleukin-6 (IL-6) to activate the JAK-STAT signaling pathway [20]. vIL-6 primarily accumulates in the endoplasmic reticulum of infected cells and activates downstream signaling by interacting with the IL-6 signal-transducing receptor gp130 [21]. This activation not only stimulates tumor cell growth but also significantly enhances malignant transformation potential through autocrine loops (particularly evident in PEL and MCD) and may inhibit apoptosis, thereby increasing tumor invasiveness and metastatic capability [21, 22]. Moreover, vIL-6 expression is closely associated with malignant transformation of tumor cells, involving interactions between multiple signaling pathways such as JAK-STAT and NF-κB [23]. Common virus-encoded proteins are summarized in Table 1.

Table 1.

Summary of viral oncogenic mechanisms.

Virus	Key oncogenic proteins	Targeted pathways/mechanisms	Clinical significance	References
EBV	LMP1, EBNA2, LMP2A	LMP1: Activates NF-κB and JAK-STAT pathways, inhibits apoptosis. EBNA2: Hijacks the NOTCH pathway to drive B-cell transformation. LMP2A: Mimics BCR signaling to escape apoptosis.	LMP1-targeted CAR-T therapy achieves an overall response rate (ORR) of 75% in EBV+ lymphoma. EBNA2 is associated with PD-L1 expression, suggesting potential for combination with immune checkpoint inhibitors.	[7, 8, 13, 61, 175]
HTLV-1	Tax, HBZ	Tax: Activates NF-κB and CREB pathways, induces genomic instability. - HBZ: Synergizes with CARD11 and upregulates oncogenes such as IRF4, BATF3, MYC, and E2F through the non-canonical NF-κB pathway.	Tax inhibitors (e.g., bortezomib) show partial efficacy in clinical trials but need to overcome drug resistance.	[29, 35, 112]
KSHV	vIL-6, LANA	vIL-6: Activates the JAK-STAT3 pathway to promote autocrine proliferation. LANA: Maintains viral latency and inhibits the p53 pathway.	Targeting the vIL-6 signaling pathway (e.g., with JAK inhibitors) may inhibit tumor growth.	[17, 20]
HBV	HBx, HBsAg	- HBx: Activates TGF-β and Wnt pathways, induces oxidative stress. - HBsAg: Integrates into the host genome, causing chromosome breakage.	HBV infection is significantly associated with non-Hodgkin’s lymphoma (especially DLBCL) epidemiologically. -Antiviral therapy (such as nucleoside analogs) can reduce the risk of lymphoma, and gene editing technology targeting HBx is being explored.	[24, 58, 200]
HCV	Core, NS3, NS5A	Core protein: Regulates lipid metabolism and inhibits the p53 apoptotic pathway NS3/NS4A: Inhibits interferon JAK-STAT signaling and promotes inflammation NS5A: Activates the Wnt/β-catenin pathway.	HCV infection is associated with marginal zone lymphoma (MZL). After HCV clearance with direct-acting antiviral agents, some patients experience spontaneous remission of lymphoma.	[27, 201, 202]
HIV	Tat, Nef	- Tat: Activates NF-κB and promotes the secretion of inflammatory factors. - Nef: Downregulates MHC-I to evade immune surveillance.	CAR-T therapy has initially shown efficacy and safety in HIV-related lymphoma. PD-L1 is highly expressed in HIV-related lymphoma (such as Burkitt lymphoma), and PD-1 inhibitors (e.g., Nivolumab) can improve survival rates.	[142, 178, 203]

Other viruses like HBV and HCV are also implicated in hematological tumorigenesis. HBV’s oncogenic mechanisms may involve its latent infection in lymphocytes and hematopoietic stem cells and interference with host immune responses [24]. It can also modulate miR-34a expression, affecting B-cell proliferation and differentiation and increasing the risk of malignant transformation [25]. In the context of HBV infection, mutations and abnormal acetylation modifications of the CREB-binding protein can further promote DLBCL development [26] (Fig. 1). The presence of HBV DNA in peripheral blood mononuclear cells suggests these cells may serve as viral reservoirs; persistent replication, especially in immunocompromised patients, may trigger hematological malignancies [24]. HCV infection may play a role in B-cell proliferative disorders by upregulating B-cell receptor (BCR) signaling. Its non-structural protein NS3/4A mediates dephosphorylation of HuR protein through interaction with CHK2, thereby regulating the post-transcriptional processes of target mRNA networks related to B-cell proliferation, ultimately affecting the BCR signaling pathway [27] (Fig. 1).

Adult T-cell leukemia/lymphoma (ATLL)

HTLV-1 is the primary cause of ATLL. By infecting T lymphocytes, the virus leads to abnormal proliferation and transformation of cells. Its oncogenic mechanisms mainly include viral gene integration, activation of intracellular signaling pathways, and suppression of host immune responses (Fig. 1). Studies indicate that HTLV-1 carriers have a significantly increased risk of developing ATLL, highlighting the importance of monitoring and early intervention for infected individuals [28]. The HTLV-1-encoded Tax protein functions as a central regulator in ATLL pathogenesis. Tax promotes the proliferation and survival of infected cells by activating multiple signaling pathways, particularly the NF-κB signaling pathway [29]. By interacting with the CREB/p300 complex, Tax disrupts cell cycle checkpoints, leading to uncontrolled cell proliferation [30]. Furthermore, Tax expression significantly increases intracellular reactive oxygen species levels, inducing gene mutations and chromosomal aberrations, causing genomic instability; concurrently, HTLV-1-infected cells exhibit reduced DNA damage repair capacity, both closely linked to Tax’s actions and collectively driving tumorigenesis [31, 32]. In ATLL patients, persistent Tax expression not only maintains NF-κB activity but also promotes interleukin-10 (IL-10) secretion, further enhancing tumor cell survival [33, 34]. Besides Tax, another key HTLV-1-encoded protein, HBZ, is also closely associated with ATLL development. HBZ synergizes with CARD11 (a protein essential for T- and B-cell activation) to upregulate the expression of oncogenes such as IRF4, BATF3, MYC, and E2F via the non-canonical NF-κB pathway, thereby inducing ATLL [35, 36]. Given the central roles of Tax and HBZ proteins in ATLL pathogenesis, intervention strategies targeting these viral proteins and their related signaling pathways (e.g., NF-κB) may represent novel therapeutic directions for ATLL, warranting in-depth investigation.

Immune escape mechanisms in virus-associated hematological malignancies

Downregulation of major histocompatibility complex (MHC) molecule expression

Viruses employ various strategies to evade immune surveillance, among which downregulating MHC molecule expression is a core mechanism. Many viruses, such as EBV, HTLV-1, HIV, and HBV, utilize this pathway to reduce T-cell recognition of infected cells [37, 38]. Specifically, the EBV-encoded oncoprotein LMP1 plays a crucial part in immune escape by regulating the expression of MHC class I molecules. Activation of the NF-κB pathway by LMP-1 upregulates the MHC class I antigen-processing pathway, yet it only induces a subdominant CD8⁺ T-cell response and evades immune recognition, thereby creating conditions for tumorigenesis and progression [39]. HTLV-1’s Tax protein, central to its oncogenesis, also achieves immune escape by interfering with antigen presentation. Tax protein acts as a transcription activator, inhibiting the expression of MHC class I molecules, impairing recognition by CD8⁺ and CD4⁺ T cells [40]. Additionally, Tax reduces antigen presentation efficiency by inhibiting interferon signaling pathways [41], making infected cells harder to clear, favoring long-term viral persistence and ultimately tumor promotion. HIV infection also causes a significant decline in MHC class I molecules, rendering infected cells “invisible” to CD8⁺ T cell surveillance [42]. HBV is also believed to have the ability to interfere with MHC expression [38]. Common mechanisms for MHC I downregulation also include epigenetic modifications, such as DNA methylation inhibiting transcription of MHC class I genes [43]. Furthermore, although interferon-gamma (IFN-γ) typically upregulates MHC I expression, its abnormal signaling pathway activation in specific pathological states (e.g., certain tumors) may paradoxically lead to MHC I downregulation, possibly related to tumor cell biology and affecting T-cell function [44].

Downregulation of MHC class II molecules is also closely linked to immune escape. Research shows that MHC-II is crucial for antigen presentation to CD4⁺ T lymphocytes, and its role in anti-tumor immunity is increasingly recognized. Reduced MHC-II molecule expression in B-cell lymphoma patients has been proven to correlate with poor survival rates [45]. This indicates that MHC II expression levels not only affect immune escape capability but may also impact prognosis. Therefore, enhancing MHC class II molecule expression through immunotherapy (e.g., combined with ICIs) may improve treatment efficacy [46]. Evidently, viruses (e.g., EBV, HTLV-1, HIV, HBV) and their encoded products (e.g., LMP1, Tax, miRNA) downregulate MHC class I and/or MHC class II molecule expression through various mechanisms (transcriptional repression, epigenetic silencing, interferon pathway inhibition), constituting a core immune escape strategy. Targeted reversal of MHC molecule downregulation to restore their expression is a highly promising new direction for future immunotherapy, including checkpoint inhibitor combination strategies (Fig. 2).

Fig. 2. Mechanisms of immune escape in virus-associated hematological malignancies.

This figure summarizes the three main strategies discussed in Section 3: (1) MHC molecule downregulation: Viral oncoproteins (e.g., EBV LMP1, HTLV-1 Tax) regulate the expression or surface presentation of MHC-I and MHC-II molecules, preventing infected tumor cells from being recognized by T cells. (2) Immune checkpoint dysregulation: Tumor cells and the microenvironment upregulate PD-1 or PD-L1. The binding of PD-L1 to receptors such as PD-1 on T cells induces T cell exhaustion and dysfunction, which is predominantly observed in HBV⁺ DLBCL and EBV⁺ HL. Concurrent upregulation of other checkpoints, including CTLA-4 and LAG-3-particularly in the context of HTLV-1 infection-further contributes to T cell exhaustion and dysfunction. (3) Regulatory T cell (Treg) induction: Immunosuppressive cytokines (e.g., TGF-β and IL-10) produced by virus-infected tumor cells (e.g., in HTLV-1 infection) promote Treg proliferation and functional activation. These Tregs suppress effector T cells through multiple mechanisms, including the secretion of immunosuppressive cytokines (IL-10, TGF-β, IL-35), expression of co-inhibitory molecules (CTLA-4, LAG-3, PD-1), and metabolic disruption, thereby facilitating immune escape. This figure was created with BioRender.com.

Regulatory role of immune checkpoint molecules

ICIs have revolutionized the treatment landscape and are now standard-of-care for a wide array of solid tumors, including melanoma, non-small cell lung cancer, and renal cell carcinoma [47]. Their integration into the management of hematological malignancies has been more gradual but is progressing rationally, driven by a growing understanding of the immune microenvironment in these cancers [48]. This trend is particularly relevant in the context of virus-associated hematological malignancies, where viral infection often creates an immunosuppressive milieu with upregulated checkpoint molecules, providing a strong biological rationale for the use of ICIs [49]. The specific mechanism is shown in Fig. 2.

PD-1/PD-L1

Aberrant expression of immune checkpoint molecules is a key factor leading to immune escape in virus-associated hematological malignancies. The programmed death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pathway plays a significant regulatory role in the TME [50]. PD-1 is primarily expressed on T cells, while PD-L1 is often overexpressed on tumor cells and certain immune cells [51]. Activation of this pathway inhibits T-cell activity, weakens their attack on tumor cells, and ultimately leads to tumor cells evading immune surveillance [1, 52]. Studies indicate that abnormal expression of the PD-1/PD-L1 pathway is closely associated with the occurrence and development of various hematological malignancies [53]. In lymphoma and leukemia patients, high expression of PD-1 and PD-L1 is often accompanied by resistance to immunotherapy, resulting in poor prognosis for these patients [54, 55]. One study has demonstrated that regulatory T cells from patients with HBV-associated DLBCL exhibit elevated PD-1 expression, and PD-1 blockade potentiates the effector functions of HBV-specific CD8⁺ T cells [56]. Furthermore, a recent clinical study has reported that in patients with HBV-associated DLBCL, the number of CD4⁺ lymphocytes significantly decreased after chemotherapy, and the CD4/CD8 ratio declined for a longer duration in this population compared to HBV-uninfected individuals, revealing the reason for the poor prognosis of HBV-associated patients: the host immune system’s tumor surveillance effect is weakened, leading to rapid disease recurrence and poor prognosis [57]. Additionally, Ren et al. has shown that CD70, TNFRSF14, and CD58 were the main mutated genes in HBV-associated DLBCL patients, leading to reduced T-cell infiltration in the TME, thereby weakening tumor immune surveillance and accelerating tumor immune escape [58, 59]. In EBV⁺ lymphoma (e.g., immunosuppression-related type III latency), EBV’ s mechanism of action varies with latency type: in cHL (type II latency), LMP1 and LMP2A (mimicking BCR signaling) jointly promote cell survival and escape from apoptosis; EBNA2 expression is closely related to tumor immune escape and proliferation [60]. Furthermore, EBV also inhibits host immune responses by upregulating programmed death-ligand 1 (PD-L1) [61], and its encoded BARF1 protein protects infected B cells from apoptosis by inhibiting apoptotic signaling pathways (e.g., regulating Bcl-2 family protein expression, enhancing anti-apoptotic Bcl-2 levels), promoting their malignant transformation [62]. Therefore, therapies targeting the PD-1/PD-L1 pathway, such as ICIs, have become a research hotspot in recent years and have shown good efficacy in the treatment of certain hematological malignancies.

Other immune checkpoints

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is another important immune checkpoint, primarily functioning in the early stages of T-cell activation [63]. CTLA-4 is an immunosuppressive molecule upregulated in the TME of DLBCL. It inhibits T-cell activation by competing with CD28 for B7 ligands [64]. This upregulation weakens the immune system’s ability to recognize and eliminate tumor cells, thereby promoting tumor growth [1, 65]. Studies show that CTLA-4 expression is increased in both regulatory T cells (Tregs) and effector T cells. This upregulated CTLA-4 can suppress anti-tumor immune responses, thereby promoting tumor growth and progression [66, 67]. High CTLA-4 expression is associated with T-cell dysfunction and an immune escape state [68]. Upregulation of CTLA-4 in T cells of HTLV-1-infected individuals leads to suppression of effector T-cell function and promotes T-cell exhaustion, a phenomenon common in chronic viral infections [69, 70]. Moreover, CTLA-4 expression positively correlates with other inhibitory markers like PD-1 and Lymphocyte-activation gene 3 (LAG-3) in T cells, indicating that in chronic viral infections, T-cell exhaustion often accompanies the activation of multiple inhibitory signaling pathways [71]. Significant CTLA-4 expression has been reported in various lymphoma subtypes, including DLBCL [72], and increased expression correlates with poor prognosis [73].

Although CTLA-4/PD-1 blockade therapy shows significant clinical effects, de novo or adaptive therapeutic resistance remains prevalent in large patient populations across different tumor types. LAG-3 is a negative regulatory molecule expressed on various immune cells [74]. Recent studies show that in the immune microenvironment of B-cell lymphoma, LAG-3 exhibits high-affinity binding with MHC class II molecules. This interaction disrupts T-cell receptor signaling transduction, inhibits T-cell activity and proliferation, and can also modulate T-cell metabolic state, promoting T-cell exhaustion and weakening the body’s immune response to B-cell lymphoma [75]. Blocking the LAG-3 pathway can restore T-cell activity and enhance anti-tumor immunity. The clinical relevance of targeting LAG-3 has been firmly established with the approval of the fixed-dose combination of relatlimab (anti-LAG-3) and nivolumab (anti-PD-1), known as Opdualag, for the treatment of melanoma [76]. This validates LAG-3 as a clinically actionable checkpoint. Inhibitors targeting LAG-3 have also shown promising efficacy in clinical trials for hematological malignancies, particularly in combination with PD-1 blockade, significantly improving tumor response rates with good tolerability [77]. This underscores the potential of incorporating LAG-3 blockade into the therapeutic arsenal for virus-associated hematological malignancies.

T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) is another emerging negative regulatory immune checkpoint that acts as a key driver in regulating immune responses and the TME. Research shows that high TIM-3 expression is closely associated with tumor immune escape, and inhibiting TIM-3 can restore T-cell function and enhance anti-tumor immune responses [78]. The efficacy of TIM-3 inhibitors in certain tumor types is promising [79, 80], and strategies combining TIM-3 with other immunosuppressive agents are being considered. Such comprehensive strategies may have synergistic effects on virus-associated hematological malignancies [81].

Induction of regulatory T cells (Tregs)

Tregs are typically defined as CD4⁺ T cells that constitutively express high surface levels of CD25 (IL-2Rα), low or no CD127 (IL-7Rα), and the transcription factor FoxP3 [82]. Tregs suppress the activity of other immune subsets. Multiple mechanisms of Treg-mediated suppression have been described, including: production of immunosuppressive cytokines such as IL-10, TGF-β, and IL-35; cytotoxicity via granzyme and perforin; expression of co-inhibitory molecules like PD-1, CTLA-4, and LAG-3; and metabolic interference through IL-2 deprivation, adenosine production, and cAMP transfer [83]. Tregs are dysregulated in the TME and are a key factor in tumor immune escape [84]. A meta-analysis of 23 previous studies including B-NHL patients showed that higher density of tumor-infiltrating Tregs correlated with better Progression-Free Survival (PFS) and Overall Survival (OS) [85]. Modulation of the cytokine milieu plays a key role in the immunosuppression process. Cancer cells release various cytokines, such as IL-6, TGF-β, and IL-10, creating a suppressive microenvironment that inhibits the activity and function of immune cells. These factors not only promote Treg proliferation but also suppress the proliferation and function of effector T cells, leading to immune escape of tumor cells [86]. This process is particularly prominent in chronic viral infections. Studies in HTLV-1 infection found that activation of the TGF-β signaling pathway in infected cells not only promoted the transformation of HTLV-1-infected cells into Treg-like cells but also enhanced their proliferation, thereby increasing their immune escape capacity [87, 88] (Fig. 2). The role of TGF-β extends beyond Treg generation to involve alterations in the immune microenvironment [89]. TGF-β helps viruses evade host immune surveillance by suppressing the function of other effector T cells [90]. This immune escape mechanism has been observed not only in HTLV-1 infection but also in other chronic viral infections like HBV and HIV [24, 37, 91].

Advanced therapeutic strategies for virus-associated hematological malignancies

Small molecule inhibitors targeting virus-encoded proteins

Small molecule inhibitors targeting EBV-encoded proteins

Latent membrane protein 1 (LMP1) protein inhibitors

LMP1 is one of the major oncogenic proteins of EBV, activating multiple signaling pathways through binding to TRAF [92]. Studies show that small molecule inhibitors targeting the TRAF-binding domain of LMP1 can effectively block LMP1 signal transduction, thereby inhibiting tumor cell proliferation and survival. For example, HSP90 inhibitors Radicicol and 17-AAG, as candidate drugs that inhibit LMP1 expression and cell proliferation, are effective in EBV-positive SNK6 natural killer (NK) cell lymphoma cells, as well as in B and T cells [93, 94]. In addition, DZ509, a specific DNAzyme targeting LMP1, can significantly inhibit the growth of nasopharyngeal carcinoma (NPC) cells both in vitro and in nude mouse models by knocking down LMP1 expression [95]; a peptide probe specifically targeting the extracellular loop domain at the N-terminus of LMP1 can also inhibit LMP1-mediated NF-κB and Akt signaling pathways, while reducing the viability and proliferation of NPC cells [96]. These preclinical studies suggest that the development of LMP1 inhibitors may provide a novel strategy for the treatment of EBV-associated tumors. The NF-κB signaling pathway is indispensable to LMP1-mediated tumorigenesis, making compounds targeting this pathway a therapeutic focus. Research has found that certain compounds like VE-821 can effectively inhibit LMP1-induced NF-κB activation, thereby reducing tumor cell proliferation and migration [97]. These inhibitors not only attenuate the pro-cancer effects of LMP1 but can also enhance the immune system’s recognition and attack of tumor cells by influencing the TME. Approximately 40% of tumor cells in lymphoma patients express LMP1 and LMP2 during latency type II, making them ideal targets for immunotherapy [98, 99].

EBNA1 protein inhibitors

EBNA1 is another key EBV protein that maintains viral latency by binding to viral DNA. Researchers have developed a series of small molecule inhibitors targeting the EBNA1 DNA-binding domain, which can significantly reduce EBNA1’s binding capacity, thereby affecting EBV replication and survival [100]. Research has revealed that some small molecules can effectively interfere with EBNA1 dimerization, thereby inhibiting its function. These molecules show good inhibitory effects not only in vitro but also effectively prevent tumor growth in vivo, indicating their potential as therapeutic agents [101]. Currently, inhibitors targeting EBNA1 are undergoing clinical trials to evaluate their efficacy and safety in treating EBV-associated tumors. For example, VK-2019, a specific inhibitor of EBNA1, has entered clinical trials, with preliminary results showing good potential in inhibiting the proliferation of EBV-positive tumor cells [102]. Progress in these clinical trials will provide new options for treating EBV-associated lymphoma.

BART miRNA inhibitors

BART miRNAs are a class of non-coding RNAs encoded by EBV that are highly expressed in EBV-associated tumors. These miRNAs participate in tumorigenesis by regulating host gene expression. Antisense oligonucleotide (ASO) strategies have been applied to target BART miRNAs, inhibiting their function and thereby affecting tumor cell growth and survival [103, 104]. Studies show that ASOs can effectively reduce the expression levels of BART miRNAs, subsequently promoting tumor cell apoptosis. Moreover, effective delivery systems are crucial for the clinical application of BART miRNA inhibitors. Researchers are exploring various delivery systems, including nanocarriers and liposomes, to improve the bioavailability and targeting of inhibitors. These delivery systems can effectively transport inhibitors into lymphoma cells, enhancing therapeutic efficacy [105]. With the advancement of nanotechnology, optimization of delivery systems will provide more possibilities for the application of BART miRNA inhibitors.

Small molecule inhibitors targeting HTLV-1-encoded proteins

Tax protein function inhibitors

CREB (cAMP response element-binding protein) and ATF (activating transcription factor) play important roles in the function of the HTLV-1 Tax protein. Studies have demonstrated that Tax activates the NF-κB signaling pathway by interacting with CREB and ATF, promoting cell proliferation and survival. Compounds blocking this interaction have potential as therapeutic strategies against HTLV-1-associated diseases. For instance, certain small-molecule inhibitors have been found to effectively block CREB binding to ATF, thereby inhibiting Tax-mediated transcriptional activation. These compounds may provide new ideas for developing novel antiviral drugs [106]. In preclinical studies, functional HDAC inhibitors targeting the Tax protein can reduce Tax expression in HTLV-1-infected cells and inhibit cell proliferation. These studies lay the groundwork for future clinical trials, suggesting that small-molecule inhibitors targeting Tax may become novel drugs for treating HTLV-1-associated diseases [107].

Tax protein degradation inducers

PROTAC (Proteolysis Targeting Chimera) is an emerging targeted protein degradation technology that utilizes its bifunctional nature to bind the target protein to an E3 ubiquitin ligase, inducing target protein degradation. For HTLV-1 Tax protein degradation, researchers have developed various PROTAC molecules that can effectively specifically target the Tax protein and mediate its degradation via the ubiquitin-proteasome system. This approach not only improves targeting specificity but also reduces the impact on normal cells and proteins, showing good application prospects [108]. Studies have shown potential for proteasome degraders targeting Tax protein (such as bortezomib) in hematological malignancies. EBV⁺ DLBCL is mostly of the activated B-cell-like (ABC) subtype, and the proteasome inhibitor bortezomib can induce apoptosis in EBV⁺ B cells [109]. Results from a prospective phase I/II study have demonstrated that bortezomib combined with R-CHP improved efficacy compared to R-CHP chemotherapy alone in treatment-naive DLBCL patients, especially those with the non-GCB subtype, with manageable safety [110]. Five-year follow-up data from the REMoDL-B study show that adding bortezomib to standard R-CHOP in treatment-naive DLBCL patients improved 5-year PFS and OS in the Activated B-Cell (ABC) and molecular high-grade subgroups, but had no effect on overall PFS and OS [111]. However, the emergence of resistance mechanisms has become a major challenge in clinical treatment. Research finds that Tax protein promotes tumor growth and survival by modulating intracellular signaling pathways, and drugs targeting it often develop resistance after a period of use. Relevant literature indicates that Tax protein resistance mechanisms are primarily related to alterations in intracellular protein degradation pathways, especially through upregulation of inhibitory factors or changes in proteasome activity to evade drug action [112, 113]. Therefore, in-depth understanding of Tax protein degradation mechanisms and finding alternative therapies to overcome resistance will be important future research directions.

Application of immune checkpoint inhibitors in virus-associated hematological malignancies

PD-1 is an inhibitory receptor expressed on the surface of T cells, while its ligand PD-L1 is typically expressed on tumor cells and certain immune cells. Activation of the PD-1/PD-L1 pathway inhibits T-cell proliferation and effector function, allowing cancer cells to evade immune surveillance. This mechanism has been extensively studied and successfully leveraged in the clinic for a variety of solid tumors [114, 115]. Its relevance is particularly pronounced in virus-associated tumors, where the frequent occurrence of high PD-L1 expression provides a strong biological rationale for the use of immune checkpoint blockade [116–119]. PD-L1 expression is relatively low in DLBCL patients (only 8.9–11.0%), while in EBV⁺ DLBCL patients, PD-L1 expression on tumor cells and in the TME is significantly higher (41.0–100.0%) [120]. PD-L1 expression correlates with EBER positivity, non-germinal center origin subtype, and poor prognosis in DLBCL patients [121]. Rituximab-containing regimens also partially rely on antibody-mediated cellular cytotoxicity. Therefore, therapeutic strategies utilizing PD-1 monoclonal antibodies targeting the immune checkpoint pathway, by restoring cytotoxic T-cell expansion and killing activity, may achieve better efficacy in EBV⁺ DLBCL patients [122]. Although PD-L1 mediates immune evasion in DLBCL, the efficacy of single-agent PD-1 blockade remains limited in relapsed/refractory cases [123]. A more effective approach may be its integration with first-line chemotherapy [124]. In 2019, Younes et al. used atezolizumab combined with R-CHOP as first-line treatment for 42 DLBCL patients. Among the 40 patients who received at least one dose of atezolizumab, the complete remission (CR) rate was 77.5%, the partial remission (PR) rate was 10%, and the 2-year PFS and OS rates were 74.9% and 86.4%, respectively. Adverse reactions were generally controllable and reversible, and efficacy was sustained [125]. When compared with historical controls from the R-CHOP arm of the GOYA study (which had a patient population with more favorable risk profiles), this regimen appeared to yield a higher CR rate (77.5% vs. 59.1%), although a formal statistical comparison with hazard ratios was not performed in this single-arm trial [126]. In 2020, a single-arm phase II study used pembrolizumab combined with R-CHOP as first-line treatment for 30 DLBCL patients. The objective response rate (ORR) and CR rates were 90% and 77%, respectively, and the 2-year PFS and OS rates were 83% and 84%, respectively, without significantly increasing the incidence of severe adverse reactions [124], suggesting that PD-1/PD-L1 monoclonal antibodies can be safely and effectively added to first-line DLBCL therapy. In this study, both EBV⁺ DLBCL patients with high PD-L1 expression (>50%) achieved CR after first-line treatment and remained progression-free [124]. Due to the lack of randomized controlled clinical trials and non-selective treatment of DLBCL patients, whether regimens containing ICIs can truly improve the prognosis of EBV⁺ DLBCL patients requires further confirmation. Currently, the favorable safety and potential efficacy of PD-1 antibodies in lymphoma treatment have attracted widespread attention. The US clinical research website shows that there are multiple ongoing clinical studies using targeted PD-1 antibody combined immunotherapy for lymphoma patients (Table 2).

Table 2.

Clinical trials of immune checkpoint inhibitors in virus-associated hematologic malignancies.

Virus	Tumor type	Immune checkpoint inhibitor	Combination therapy	Trial design	Number of patients	Key clinical outcomes	Source
EBV	EBV+NHL	Nivolumab	/	Phase 2	40	Trial ongoing, data pending	NCT03258567
	EBV+ Lymphoma	Nivolumab	EBV-specific cytotoxic T lymphocytes	Phase 1	8	Results not yet available	NCT02973113
	Extranodal NK-T cell lymphoma, Nasal Type	Tislelizumab	Involved-site radiotherapy	Phase 2	30	Trial ongoing, data pending	NCT05149170
	Early-stage NK/T cell lymphoma	Anti-PD-1 antibody	Peg-Asparaginase Chidamide	PHASE 2	35	Trial ongoing, data pending	NCT04414969
	Extranodal NK/T cell lymphoma, Nasal Type	Anti-PD-1 antibody	Pegaspargase Definitive IMRT	PHASE 2	30	Results not yet available	NCT04676789
	Extranodal NK-T cell lymphoma	Anti-PD-1 monoclonal antibody	Pegaspargase Gemcitabine	PHASE 2	35	Results not yet available	NCT05254899
	Extranodal Natural Killer T Cell Lymphoma	Anti-PD-1 antibody	Chidamide Pegaspargase DDGP	PHASE 3	142	Trial ongoing, data pending	NCT06255795
HIV	HIV+ NHL	Pembrolizumab	ART	PHASE 1	58	ORR 62.1% (87.5% in treatment-naïve); mPFS 28.2 mos	NCT02595866
HTLV	HTLV-associated ATLL	Nivolumab	/	PHASE 2	3	No objective responses observed	NCT02631746

PD-L1 is expressed in 39–100% of nasal-type extranodal NK/T-cell lymphoma (NKTCL) patients [127]. PD-L1 is the ligand of PD-1, commonly upregulated by EBV-driven LMP1. It triggers NF-κB and MAPK signaling pathways, making the anti-PD-1/PD-L1 axis a potent immunotherapeutic target [128, 129]. Evidence suggests that serum PD-L1 levels correlate with poor prognosis in ENKTCL-NT patients [130]. Recently, prospective and retrospective clinical studies have shown that blocking the PD-1/PD-L1 axis is a safe and robust treatment for ENKTCL-NT, demonstrating strong activity, especially in relapsed/refractory disease [131, 132]. For instance, in the phase 2 ORIENT-4 trial, sintilimab achieved an ORR of 75.0% and a 2-year overall survival of 78.6%, with a median OS not reached—markedly superior to historical controls in which the median OS was only 4.8 months [131]. Many PD-1 and PD-L1 monoclonal antibodies, as well as the dual-targeting anti-PD-1/PD-L1 antibody IBI318, have been studied in ENKTCL-NT [133]. Combining anti-PD-1/PD-L1 antibodies with other innovative therapies, such as combining sintilimab with chidamide, has been shown in a single-arm, non-randomized phase Ib/II clinical trial to improve anti-tumor efficacy in relapsed/refractory NKTCL, with an ORR of 58.3%, CR rate of 44.4%, and good safety [134]. Additionally, anti-PD-1/PD-L1 therapy may also synergize with cell therapy or other treatment strategies [135]. Combination regimens with different anti-tumor mechanisms may improve prognosis.

The role of PD-L1 in the pathogenesis of ATLL is increasingly recognized, though its full implications remain to be fully elucidated [136]. Studies show that ATLL tumor cells typically express high levels of PD-L1. This expression, by binding to PD-1 on T cells, inhibits T-cell activation and function, leading to immune escape phenomena, thereby promoting tumor growth and metastasis [137]. A study of 135 ATLL patients found that PD-L1-positive lymphoma cells were associated with significantly shorter median survival (7.5 vs. 14.5 months) and identified as an independent poor prognostic factor for overall survival (P = 0.0322) via multivariate analysis [138]. Notably, the functional consequences of blocking the PD-1/PD-L1 axis may depend on the specific agent used. For instance, one study has shown that PD-L1 expression impairs the anti-tumor activity of CD22-CAR-T cells, and this inhibition could be rescued by anti-PD-L1 antibodies, but not by anti-PD-1 antibodies [139], suggesting potential functional differences between these two classes of inhibitors. However, single-agent therapy with PD-1 inhibitors (e.g., nivolumab) for ATLL has exhibited poor clinical efficacy; in some cases, it may even drive disease progression by abnormally activating immune pathways [140]. Consequently, the research focus has shifted toward combination therapies, such as combining ICIs with cytokine therapy (e.g., IL-2), which may synergistically enhance T cell function and persistence in the TME [141].

For HIV-associated lymphomas, studies show that PD-1 inhibitors can significantly improve patient survival rates [24, 142]. Intervention in the PD-1/PD-L1 pathway can effectively overcome this obstacle, enhancing the immune system’s ability to recognize and clear tumor cells [143]. Studies have shown clinical benefit with pembrolizumab in various tumors including HIV-associated non-Hodgkin lymphoma, with acceptable safety [144]. For cancer patients with HIV receiving ART and CD4⁺ T cell counts greater than 100 cells/μL, Pembrolizumab has acceptable safety but may be associated with KSHV-related B-cell lymphoproliferation [144]. During KSHV infection, PD-L1 expression is significantly upregulated, primarily related to the viral latent and lytic cycles [145]. Studies show that PD-1/PD-L1 inhibitors can effectively inhibit the proliferation of KSHV-infected cells. Blockade of the PD-1/PD-L1 pathway can enhance T cell anti-tumor activity, thereby reducing tumor burden and spread [145, 146]. High PD-L1 expression correlates positively with clinical response in patients, especially those receiving immunotherapy, where higher PD-L1 expression levels are associated with greater efficacy [147–149].

Furthermore, clinical trials targeting specific populations are advancing. For example, in liver cancer patients, the combination of PD-1 inhibitors with standard chemotherapy shows promising prospects, particularly for HBV-associated hepatocellular carcinoma patients, where PD-1 inhibitor application demonstrates potential therapeutic advantages [150, 151]. These studies further emphasize the importance and future application potential of ICIs in virus-associated hematological malignancies. Previous studies have shown that the incidence of PD-1 expression in HBV-associated DLBCL patients was 4.3 times that of HBV-uninfected individuals (40.0% vs. 9.4%, p = 0.010) [152]. Furthermore, PD-1-positive HBV-associated DLBCL patients have a lower median OS and PFS. A retrospective study shows that PD-1-positive patients in the HBsAg-positive group have the worst median OS and PFS (24 months and 9 months, respectively), while PD-1-negative patients in the HBsAg-negative group had the best median OS and PFS (not reached and 32 months, respectively) [152]. These results suggest that the poor prognosis of HBV-associated DLBCL patients may be related to the high rate of PD-1 expression.

Oncolytic viruses (OV)

OVs are natural or genetically modified viruses with anti-tumor and anti-viral activity, possessing tumor tropism that allows them to target and kill cancer cells without harming normal cells [153]. OVs have demonstrated significant selective replication and tumor regression effects in EBV⁺ DLBCL models. Oncolytic viruses have the ability to directly lyse tumor cells while simultaneously activating the host’s immune response, thereby enhancing anti-tumor effects [154]. A phase I clinical trial (NCT02962167) specifically evaluated the safety and efficacy of the oncolytic herpes simplex virus type 1 (HSV-1) T-VEC in EBV⁺ DLBCL patients. Preliminary results from this study show that some patients achieve objective responses after treatment, providing important clinical justification for oncolytic virus application. Through natural interactions between the virus, tumor cells, and the immune system, oncolytic viruses can attack and kill cHL cells [155]. Bollard et al. designed autologous cytotoxic T lymphocytes (CTLs) targeting LMP1 and LMP2. Among 29 high-risk or multiply relapsed patients receiving LMP-CTLs as adjuvant therapy, 28 (96%) achieved sustained remission with no virus therapy-related toxicity observed after CTL infusion (median remission time 3.1 years) [156]. Oncolytic viruses can also enhance the anti-tumor effect of ICIs in relapsed/refractory cHL. As demonstrated in several ongoing clinical trials for solid tumor patients, oncolytic HSV-1 can improve the clinical benefit of ICIs without overlapping toxicity profiles [157–159]. It can also induce systemic or abscopal effects and make distal tumors increasingly susceptible to ICI therapy by increasing T cell recruitment and immune cell activation [160]. OVs also increase the expression of PD-1 and other checkpoint molecules on immune cells. Approximately 30% of infused DNRII-T cells expressed PD-1 [90]. Among various viral therapeutic perspectives for treating relapsed/refractory HL patients, the primary approach targets the viral proteins LMP1 and LMP2. Further research is necessary to evaluate the potential role of OV therapy in HL treatment.

Virus-specific T-cell therapy (VST)

Viral infections following hematopoietic stem cell transplantation (HSCT) are important factors affecting patient prognosis and survival, particularly due to the significantly increased incidence of complications like cytokine release syndrome (CRS) and graft-versus-host disease (GVHD) [161]. Common viral infections include EBV, adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6). In recent years, VST therapy has shown promising prospects in the prevention and treatment of these viral infections, emerging as a novel therapeutic approach. Post-HSCT, appropriate antiviral therapy and immune monitoring are crucial. Studies indicate that VST can effectively control the replication of viruses like CMV and EBV, reduce viral load, and thereby improve patient prognosis [162]. Using VST from third-party sources can, to some extent, restore the function of virus-specific T cells, thereby enhancing immune response efficacy [163]. A phase II clinical trial enrolled 38 patients involving 45 infections. Results showed that a single infusion of VSTs produced a 92% CR or PR rate. Overall, viral clearance rates were: 100% for BKV, 94% for CMV, 71% for AdV, 100% for EBV, and 67% for HHV-6 [164]. Furthermore, VST therapy demonstrated good safety regarding GVHD incidence, with only a few patients experiencing severe GVHD symptoms. This effect is primarily attributed to VSTs’ ability to precisely recognize and target virus-infected cells while minimizing impact on healthy cells [165, 166]. In a retrospective study, VST showed significant therapeutic effects in patients with EBV reactivation, effectively controlling viral load and improving clinical symptoms [167]. VST therapy has been proven to have potential therapeutic effects in patients with EBV-associated lymphoma, with growing clinical evidence supporting its broader application [168]. Representative studies include: (1) Bollard et al. designed a type of CTL expressing a dominant-negative TGF-β receptor type II (DNRII-T cells). DNRII-T cells expanded and persisted for up to 4 years in patients with EBV-positive relapsed/refractory cHL. Four out of seven patients with active disease had clinical responses, with two patients maintaining sustained clinical responses after 4 years [90]. (2) In relapsed/refractory extranodal NK/T cell lymphoma (ENKTCL), the infusion of autologous EBV-specific T cells (ballaleucel-T) has been shown to induce remission. Similarly, adoptive transfer of EBV LMP1/2-specific CTLs has demonstrated sustained clinical efficacy in maintaining remission for ENKTCL patients and is a validated treatment option for EBV-positive cHL [169, 170]. (3) Beyond these settings, autologous LMP-specific CTLs have proven capable of inducing sustained remission with minimal toxicity in individuals with relapsed or refractory EBV-associated lymphoma [171], highlighting the broader applicability of this strategy beyond the post-transplant setting. (4) Further reinforcing these findings, autologous T cells targeting EBV LMPs have shown safety and efficacy in treating type 2 EBV-associated lymphoma patients, especially those who failed standard therapies (including high-dose chemotherapy followed by autologous stem cell rescue). The 2-year overall survival rate was 68%. LMP-Ts are a safe and effective treatment to prevent relapse in EBV-associated lymphoma patients post-transplant and support their use as adjuvant therapy to improve post-transplant outcomes [172]. Moreover, in the context of chronic active EBV disease, the immune system is severely suppressed by EBV infection, placing patients at high risk of malignancy development. Studies show that with VST treatment, many patients exhibit significantly decreased viral loads and improved clinical symptoms after treatment. VSTs are proven safe and effective, especially for patients with primary immunodeficiency [173]. Following VST treatment, tumor burden significantly decreased in some patients, and survival rates improved.

Chimeric antigen receptor T-cell (CAR-T) therapy

CAR-T therapy is a revolutionary immunotherapy approach, particularly demonstrating immense potential in treating hematological malignancies. The core of this therapy lies in genetically engineering a patient’s own T cells into CAR-T cells capable of recognizing and attacking tumor cells [174]. CD19 CAR-T is already used to treat B-cell malignancies. Studies have reported the efficacy of CAR-T cells targeting LMP1 and gp350 in EBV⁺ malignancies [175, 176]. The use of CD19 CAR-T cells for treating EBV⁺ DLBCL is still under exploration. CAR-T therapy has been approved for treating relapsed/refractory B-cell lymphoma in the second line and beyond [177]. However, for HIV-associated lymphoma, current data are limited to case reports, as people living with HIV were not included in pivotal trials. To date, there are reports of 6 HIV-associated lymphoma patients treated with CAR-T. Among them, 3 patients achieved CR, and 1 patient achieved PR [178]. This result suggests that CAR-T therapy may have efficacy in HIV-associated lymphoma patients, although immune-related adverse reactions still require attention during treatment.

Research by Tang et al. indicates that using HELA/CAR cells targeting LMP1 provides a promising cell therapy for EBV-positive malignancies [109]. In recent preclinical studies, four CAR-T cell lines (CD38-CAR, LMP1-CAR, and its tandem variant CAR 2) demonstrated significant cytotoxicity against NKTCL cells both in vitro and in vivo [179]. CD38-CAR-T cells showed significant inhibitory effects on NKTCL in vitro and in mouse xenograft models [180]. Furthermore, investigations found that NKTCL cells highly express B7-H3, and both anti-B7-H3/CD3 bispecific T cells and B7-H3-redirected CAR-T cells exhibited potent anti-tumor efficacy in preclinical studies [181].

HBV-associated DLBCL patients receiving CAR-T therapy did not have an increased risk of severe CRS [182]. However, research by Yang et al. has shown that HBV-associated DLBCL patients receiving CD19-CAR-T therapy are at risk of HBV reactivation, especially in HBeAg-positive patients; close monitoring of HBV-DNA levels and adequate antiviral prophylaxis are crucial for preventing HBV reactivation [183]. HBV-associated lymphomas exhibit mutations in immune escape-related genes such as CD70, CAR-T targeting CD70 may have potential efficacy.

Despite some clinical successes, the application of CAR-T therapy in virus-associated hematological malignancies still faces numerous challenges. Among these, viral infection may impair T cell function, reducing CAR-T efficacy [184]. Additionally, the immunosuppressive nature of the TME negatively impacts the anti-tumor effects of CAR-T. Tumor cells may evade immune attack by expressing inhibitory molecules like PD-L1, which significantly diminishes treatment efficacy [185]. Therefore, enhancing the efficacy and persistence of CAR-T is a research priority, with many strategies being explored, including combining with other immunotherapies and improving CAR construct design. The advantage of CAR-T therapy lies in its customizable nature, targeting patient-specific tumor markers while achieving durable anti-tumor effects by activating the patient’s own immune system [186, 187]. However, the complexity of treatment and potential side effects (such as CRS and neurotoxicity) are also key issues requiring close monitoring [188, 189]. Therefore, researchers are striving to develop safer and more effective CAR-T cell therapies and explore ways to enhance persistence by modulating T cell memory properties.

Therapeutic vaccines

The application of therapeutic vaccines in virus-associated hematological malignancies is centered on activating specific T cell immunity through the delivery of viral antigens to achieve long-term anti-tumor effects; in terms of target selection, EBV-associated tumors primarily target LMP1/LMP2 (which mediate latent infection) and EBNA1 (which maintains the viral genome) [190, 191], while HTLV-1-associated ATLL focuses on the Tax protein (a viral transcriptional activator) as the key target antigen [192], with delivery strategies including dendritic cell (DC) vaccines (e.g., autologous DCs loaded with Tax peptides to enhance antigen presentation) [193], mRNA vaccines (e.g., WGc-043 injection encoding EBV-LMP1/LMP2, the world’s first mRNA vaccine for EBV-associated tumors), and viral vector vaccines (e.g., modified vaccinia Ankara (MVA) carrying EBNA1/LMP2 fusion protein to activate CD4⁺/CD8⁺ T cells) [194]; in terms of clinical research progress, for EBV-associated lymphomas (such as cHL, NK/T-cell lymphoma), LMP-specific CTL therapy in 50 EBV⁺ lymphoma patients showed that the 2-year event-free survival rate of high-risk/relapsed patients (n = 29) reached 82%, 13 of the active disease patients (n = 21) had clinical responses (11 with complete remission), and the responding patients had “epitope spreading” to generate T cells against non-viral tumor antigens, with no infusion toxicity and no need for lymphodepletion preconditioning [171], while DC vaccine combined with CTL activated T cells through EBV peptide-pulsed DCs, significantly reducing serum EBV DNA levels and inducing tumor regression in NPC patients [195, 196]; for HTLV-1-associated ATLL, Tax-DC vaccine treated 3 patients, all of whom had improved PS scores without severe adverse reactions, 2 achieved partial remission within 8 weeks, 1 later converted to complete remission, 1 had stable disease for 14 months, and Tax-specific CTLs peaked at 16–20 weeks with a decrease in sIL2R levels, confirming its clinical potential for the first time [193]; in terms of innovative vaccine strategies and technological breakthroughs, mRNA vaccines such as WGc-043, the world’s first EBV tumor mRNA vaccine, have been approved for clinical trials in China and the United States, with advantages such as high immunogenicity and no risk of genomic integration, and its clinical trial NCT05714748 is evaluating its efficacy in EBV infection-related gastric cancer; virus-like particle (VLP) vaccines mimic viral structures without genetic material and have high safety, such as EBV VLPs with knocked-out oncogenes inducing potent immune responses in mice [197]; multi-target combination vaccines address the bottleneck of preventive vaccines, adopting a new strategy combining gp350⁺ gH/gL/gB fusion proteins to cover B-cell/epithelial cell infection pathways [198], while previous gp350 monomer vaccines only prevented infectious mononucleosis (78% efficacy) and were ineffective against asymptomatic infections [199]; current challenges include antigen expression heterogeneity (e.g., Tax expression loss in some ATLL tumor cells, requiring combination with demethylating agents to enhance antigen presentation), immunosuppressive microenvironment (needing combination with immunomodulators such as mogamulizumab or PD-1 inhibitors), and long-term maintenance of immune responses (needing optimized booster strategies), future directions involve developing multi-antigen mRNA/VLP vaccines to enhance immune coverage, combining with ICIs or epigenetic drugs to overcome tumor escape, and exploring preventive applications in high-risk populations (such as EBV⁺/HTLV-1⁺ carriers), overall, therapeutic vaccines targeting EBV (LMP1/LMP2) or HTLV-1 (Tax) viral antigens have demonstrated safety and clinical potential in lymphomas and ATLL. The various treatment strategies mentioned above are presented in Fig. 3.

Fig. 3. Therapeutic strategies for virus-associated hematologic malignancies.

(1) Small-molecule inhibitors targeting viral proteins: inhibitors targeting LMP1, EBNA1 proteins and BART miRNAs; compounds that inhibit the function of Tax protein or induce its degradation. (2) Immune checkpoint inhibitors: mainly PD-1/PD-L1 inhibitors, with CTLA-4/LAG-3/TIM-3 inhibitors as potential directions. (3) Therapeutic vaccines: including dendritic cell vaccines (loaded with Tax peptides to enhance antigen presentation), mRNA vaccines (the world’s first tumor vaccine WGc-043 targeting EBV-LMP1/LMP2), and viral vector vaccines (MVA carrying EBNA1/LMP2 fusion protein to activate T cells). (4) Oncolytic virus (OV) therapy: exerts anti-tumor effects by enhancing PD-1 expression, recruiting T cells and activating immune cells. (5) Virus-specific T-cell therapy (VST): controls the replication of viruses such as EBV/CMV after transplantation and reduces the load; restores the function of virus-specific T cells and improves immune response; effectively reduces the risk of cytokine release syndrome (CRS) and graft-versus-host disease (GVHD). (6) CAR-T therapy: applied to subtypes such as EBV⁺DLBCL, HIV/HBV-related lymphoma and NKTCL. This figure was created with BioRender.com.

Conclusions and perspectives

The occurrence and development of virus-associated hematological malignancies is a complex, multi-factorial, multi-stage process involving virus-mediated molecular carcinogenic mechanisms and tumor cells evading host defenses through sophisticated immune escape strategies. This review has delineated the intricate interplay between oncogenic viruses and the host immune system, summarizing the landscape of advanced therapeutic approaches, including viral protein-targeting agents, ICIs, oncolytic viruses, VST, CAR-T therapy, and therapeutic vaccines.

While these novel therapies hold substantial promise, their efficacy is frequently constrained by the profoundly immunosuppressive TME-an obstacle that can inactivate infused cytotoxic cells and foster treatment resistance. Additionally, several key challenges persist: antigenic heterogeneity and loss, which enable tumors to evade targeted therapies such as CAR-T and VSTs; the logistical and financial complexities associated with manufacturing personalized cell therapies; and the risk of unique adverse events, including viral reactivation and severe CRS. Furthermore, patients with underlying chronic viral infections have often been underrepresented in pivotal clinical trials, resulting in critical gaps in our understanding of optimal management strategies for this patient population.

The key to overcoming these challenges lies in the rational design of multi-mechanism combination therapeutic strategies. Future research should focus on integrating different modalities, such as combining ICIs with cellular therapies to reverse T cell exhaustion, or pairing epigenetic modulators with therapeutic vaccines to reverse viral antigen silencing. The development of “off-the-shelf” allogeneic cell products and next-generation multi-targeting agents will be crucial to improve accessibility and efficacy. Concurrently, advancing biomarker-driven patient stratification will be paramount for personalizing therapy. Through such interdisciplinary collaboration and technological innovation, the field can move decisively from disease control towards personalized medicine and functional cures for patients with virus-associated hematological malignancies.

Author contributions

TTL performed the selection of literature, drafted the paper. ZLY and JL prepared the figures. CYW and QX collected the related references and organized the tables. XMZ conceived the manuscript. YL designed and edited the manuscript.

Data availability

No datasets were generated or analysed during the current study. All data discussed or summarized are derived from previously published studies, which are cited in the reference list.

Competing interests

The authors declare no competing interests.