New horizons in B-cell lymphoma immunotherapy: From immune checkpoints to precision medicine

Abstract

B-cell lymphoma, a malignancy in hematology with high heterogeneity, has its genesis and progression intricately associated with immune system regulation. Over the past three decades, transformative breakthroughs in B-cell malignancy investigations have emerged through paradigm-shifting molecular discoveries. Nevertheless, numerous hurdles persist in attaining a comprehensive understanding and effective treatment of this disease. Novel chemotherapeutic strategies demonstrate promising potential in B-cell lymphoma management, particularly through targeting immune checkpoints such as PD-1 (Programmed Cell Death Protein 1), LAG-3 (Lymphocyte-activation Gene 3), TIM-3 (T-cell Immunoglobulin and Mucin-domain containing-3), and TIGIT (T-cell Immunoreceptor with Ig and ITIM Domains) play pivotal regulatory roles within the immune system. These molecules critically orchestrate immune cell activation dynamics, proliferative capacity, and effector functions, thereby preserving immunological homeostasis. Deciphering the functional architecture of co-inhibitory checkpoints (e.g., PD-1/CTLA-4) in lymphomagenesis serves dual imperatives: deconstructing tumor immune evasion programs while establishing conceptual frameworks for precision immunotherapeutics development. PD-1 engagement with PD-L1/PD-L2 impairs T lymphocyte activation, facilitating tumor immune evasion. Deciphering these molecular processes enables therapeutic agents to employ targeted blockade strategies to restore antitumor immunity in lymphomas. Moreover, in-depth research on these checkpoints holds great promise for the discovery of novel biomarkers. These biomarkers may help predict responses to immunotherapy in lymphoma patients. This would enable clinicians to tailor personalized treatment plans for each patient, maximizing the therapeutic efficacy while minimizing unnecessary side-effects. Certain genetic signatures related to these immune checkpoints might be identified as predictors of a favorable response to PD-1 inhibitor-based immunotherapy. This analysis systematically deciphers the molecular interplay of PD-1/LAG-3/TIM-3/TIGIT immune checkpoint axes, delineating their regulatory dynamics in B-cell lymphomagenesis. It systematically summarizes the current research achievements, delves into the existing problems, and explores the future research directions. This approach seeks to advance dual contributions to fundamental science and clinical application in B-cell lymphoma immunotherapy, thereby facilitating therapeutic innovations while deepening mechanistic comprehension of disease pathogenesis. By doing so, it aims to provide valuable insights for both basic research and clinical translation in the field of B-cell lymphoma immunotherapy, ultimately enabling advancements in patient care and deeper insights into this multifaceted condition.

Introduction

Lymphomas are classified into two major subtypes: Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), both encompassing clonally derived lymphoproliferative malignancies with significant biological heterogeneity. Notably, B-cell lymphomas constitute approximately 95 % of global lymphoma incidence [1]. Diffuse large B-cell lymphoma (DLBCL), the globally predominant adult lymphoma variant, accounts for approximately 30 % of annual newly diagnosed NHL cases [2]. B-cell lymphoma commonly manifests as lymph node enlargement and extranodal lesions, with systemic dissemination frequently leading to infiltration of visceral organs such as the liver, spleen, or bone marrow [3]. The CHOP regimen (rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone), an established first-line therapy, achieves durable remission in approximately two-thirds of DLBCL patients, but relapsed/refractory cases show poor response to conventional therapies, and the prognosis remains poor, with a low 5-year survival rate. Although radiotherapy can effectively control local tumors, it also inflicts certain damage on surrounding normal tissues and has limited efficacy in treating systemic lymphoma. Hematopoietic stem cell transplantation is restricted by factors such as donor sources, transplantation-related complications, and the physical condition of patients, and not all patients are eligible [4].

With the continuous in-depth exploration of the tumor immune escape mechanism, immunotherapy has gradually emerged as a research hotspot and a new breakthrough direction in the field of tumor treatment. Immunological checkpoints are a crucial mechanism in the immune system that can regulate immune responses and maintain immune homeostasis [5]. The functions of immunological checkpoints include recognizing and eliminating tumor cells, clearing virus-infected cells, and maintaining self-immune tolerance. Common immunological checkpoints involve T cell surface antigen receptors, B cell surface antigen receptors, immunosuppressive proteins, and cytokine receptors. However, malignant cells develop diverse strategies to evade immune detection and elimination. These cells may mask their presence by suppressing antigen-processing pathways or blocking immune cell infiltration into tumor sites [6,7]. They can also establish an immunosuppressive microenvironment through mechanisms including releasing and upregulating production of immunosuppressive cytokines (e.g., IL-10, TGF-β), attracting immunosuppressive cell populations (Tregs, MDSCs, M2 macrophages), and disrupting metabolic pathways of immune cells [[6], [7], [8]]. A critical oncogenic strategy involves the dysregulation of immunoregulatory checkpoints to subvert host defense mechanisms [9]. These immunomodulatory axes are mediated by specific molecular interactions that suppress cytolytic activities of T lymphocytes and NK cells upon engagement, thus compromising antitumor immunity. Therefore, by inhibiting these immunological checkpoint molecules, therapeutic augmentation of antitumor immunity represents a viable strategy, achieving the goal of treating tumors [10]. Currently, the prevalent immunological checkpoints in lymphoma are programmed death protein (PD-1), key immunoregulatory molecules include LAG-3 (lymphocyte-activation gene 3 protein) and TIM-3 (T-cell immunoglobulin and mucin-domain containing-3), and TIGIT (T cell immunoglobulin and ITIM domain). These molecules bind to ligands on tumor cells or other inhibitory cells, inhibit immune cell activation or function, leading to immune evasion and disease initiation [9,11].

In recent years, immunological checkpoint inhibitors, a treatment strategy targeting these molecules, enhance immune cell activation and function by blocking checkpoint molecular signaling pathways, thereby improving tumor immunotherapy efficacy. They have become a crucial immunotherapy approach. By blocking checkpoints to boost immune responses, they can be used in treating tumors and infectious diseases [12]. When considering B-cell lymphocytic malignancies, traditional therapeutic approaches such as R-CHOP chemotherapy have achieved limited success in relapsed/refractory cases, underscoring the urgent need for novel treatment strategies. Immunological checkpoint inhibitors (ICIs), targeting critical pathways including PD-1/PD-L1, LAG-3/MHC-II, TIM-3/galectin-9, and TIGIT/CD155, have emerged as transformative agents by reinvigorating antitumor immunity. This work systematically integrates contemporary evidence delineating PD-1/LAG-3-mediated immunosuppressive networks in B-cell malignancy niches, while critically appraising translational breakthroughs in checkpoint-targeted interventions and highlights unresolved questions. By integrating mechanistic insights with translational research, offers an innovative therapeutic strategy for lymphoma management.

Immunological checkpoint molecules: Basic biological features

Molecular biological characteristics of PD-1

The augmented tumor immune responses via PD-1 inhibition were initially observed in persistent infection paradigms, wherein PD-1/PD-L1 axis disruption ameliorated T lymphocyte exhaustion [[13], [14], [15]]. Extending these observations, accumulating studies demonstrate PD-1 inhibition selectively disrupts T cell PD-1 and tumor PD-L1 binding, consequently reinstating T lymphocyte-dependent antitumor responses. Morphologically, PD-1 (CD279) features an extracellular IgV domain and is mainly localized to activated T lymphocytes, B lymphocytes, and natural killer cells [16]. The predominant ligand in tumor immunology, PD-L1, exhibits ubiquitous expression on neoplastic cells, antigen-presenting cells, as well as select normal tissue compartments [17].

The PD-1/PD-L1 signaling axis constitutes a central immunoregulatory circuit that attenuates T cell effector activity and sustains immune tolerance in physiological contexts [18,19]. Concomitantly, MHC class I on APCs and tumor cells delivers antigenic peptides to PD-1hi CD8+ T lymphocytes. TCR-mediated antigen detection triggers CD8+ T cell activation, inducing cytotoxic activity. Upon activation, T lymphocytes secrete interferon-gamma (IFN-γ) that engages the cognate IFN-γ receptor on malignant cells, initiating the JAK1 or IAK2-STAT1 signaling cascade. This pathway upregulates chemokines including CXCL9/CXCL10, chemokines pivotal for T-cell trafficking It is noticeable that, neoplasms with JAK1 loss-of-function (LOF) mutations demonstrate compromised CXCL9/10 expression, resulting in diminished T lymphocyte infiltration. Furthermore, IFN-γ signaling induces IRF-1 (interferon regulatory factor 1), enhancing PD-L1 gene transcription in tumor cells [20,21].(Fig. 1.a)

Fig. 1.

a. Tumor antigens processed by APCs activate CD8⁺ T cells, which release IFN-γ. IFN-γ binding to tumor cell IFN-γR activates JAK1/2-STAT1 signaling, inducing RF-1-mediated PD-L1 gene transcription. PD-L1 overexpression triggers PD-1 binding on T cells, where ITIM/ITSM phosphorylation recruits SHP1/SHP2 to dephosphorylate ZAP70, suppressing MAPK-AKT signaling and T-cell proliferation/activation while inducing metabolic reprogramming. b. LAG-3 binds MHC-II to disrupt TCR signaling, blocking T-cell activation. Its interaction with Galectin-3 induces receptor dimerization, recruiting SHP-1 and CD39 to suppress T-cell activity. LSECtin binding impedes antitumor effector T-cell proliferation, while FGL1 engagement enhances tumor growth and metastasis. c. Unliganded TIM-3 associates with BAT3 and LCK, amplifying T-cell responses. Ligand binding (e.g., Galectin-9, CEACAM1) phosphorylates Tyr256/263, displacing BAT3 to enable TIM-3 inhibition via FYN-PAG-CSK-mediated LCK inactivation. TIM-3 also recruits CD45/CD148 phosphatases, destabilizing immunological synapses and dampening T-cell effector functions. d. TIGIT, expressed on T/NK cells and Tregs, binds CD155 to exert immunosuppression: directly inhibiting T cells via CD155 ligation; skewing APC cytokine profiles (up-regulation IL-10 and down-regulationIL-12); outcompeting CD226 activation. Treg-TIGIT enhances suppressive activity, while F. nucleatum Fap2 engages TIGIT to reinforce inhibition. Intrinsically, TIGIT curtails T/NK cell proliferation, cytokine release, and cytotoxicity.

PD-L1/PD-1 binding induces conformational changes in PD-1, leading to phosphorylation of its intracellular ITIM/ITSM motifs. Subsequently, SHP2/SHP1 phosphatases are recruited, dephosphorylating ZAP70 (a 70-kDa zeta-chain-associated protein kinase). This cascade inhibits MAPK and AKT pathway activation, suppresses TCR-driven IL-2 synthesis, thereby disrupting T-cell proliferative capacity and effector functionality (Fig. 1.a).

Dysregulation of the MAPK signaling cascade modulates cellular functions including proliferation, differentiation, apoptotic regulation, and stress adaptation in downstream cell populations. For instance, in tumor cells, inhibiting the PD-1/PD-L1 molecular cascade augments MAPK signaling activity. Thereby inducing dual pro-apoptotic or immunostimulatory effects, with research demonstrating resultant T-cell metabolic reprogramming, such as decreased glucose uptake and oxidative phosphorylation ability [22]. SHP2 translocation to TCR-proximal microdomains attenuates TCR-mediated signaling fidelity while suppressing PI3K/AKT axis activation, thereby establishing a pro-survival niche for malignant clones [23,24]. Another signaling pathway, PLCγ1. DAG and IP3 synthesis induces ER calcium mobilization, driving NFAT/CREB nuclear translocation and upregulating IL-2 gene expression.

IL-2 exerts dual roles in antitumor immunity. This process facilitates CD8+ T-cell activation and induces tumor cell apoptosis, while concurrently promoting the expansion of regulatory T cells (Tregs), which inhibit anti-tumor immunity [25]. The net effect of IL-2 is dictated by the balance between effector and regulatory T-cell populations. Additionally, APCs stimulate the differentiation of CD4+ T cells into Th1 subsets via MHC class II-TCR interaction, stimulating release of IFN-γ, TNF-α cytokines and cytotoxic perforin (PFN), and granzyme B (GZMB). Among these, IFN-γ can stimulate the activation and proliferation of macrophages and also enhance the activity of NK cells, strengthening their phagocytosis and killing ability of tumor cells. IFN-γ-mediated anti-angiogenic effects lead to tumor vasculature regression, thereby compromising neoplastic nutrient acquisition and ultimately restraining tumor progression and metastasis. The concomitant secretion of TNF-α, PFN and GZMB collectively mediates tumor cell apoptosis through distinct molecular pathways [[26], [27], [28]].

Beyond PD-1/PD-L1, at least five additional membrane proteins—PD-L2, RGM-2, B7-1 (CD80), and others—interact within this signaling network [29]. However, their relative contributions to T-cell activation versus inhibition remain poorly defined, necessitating further mechanistic studies to optimize therapeutic targeting.

Molecular biological characteristics of LAG-3

While CTLA-4/PD-1 blockade exhibits significant clinical efficacy, de novo or adaptive therapeutic resistance remains prevalent in substantial patient cohorts across diverse tumor types [30]. LAG-3 is detected across multiple immune cell populations, including CD4+Foxp3+ Tregs, Tr1 cells, B lymphocytes, plasmacytoid DCs (pDCs), and specific NK cell subsets [31,32]. Residing on chromosome 12, LAG-3 functions as a type I transmembrane protein. Positioned next to the CD4 gene, it exhibits 20 % sequence homology with CD4. Structurally, it consists of an extracellular region, a connecting protein, and an intracellular region. The extracellular region features four immunoglobulin-like domains (D1–D4) structural stabilization via eight Cys residues and four N-glycosylated modifications [33].

Specifically, D1 exhibits a V-set immunoglobulin structure, while D2–D4 are classified under the C2-set immunoglobulin superfamily, encoded by exons II–VI. The intracellular domain includes two critical motifs: the 'KIEELE' motif, containing a lysine residue that acts as a pivotal inhibitory modulator of T-cell activation [34], and the glutamate-proline (EP) repeat, implicated in signal transduction [35].

While the intracellular domain of LAG-3 modulates T-cell proliferation and cytotoxic activity [36], the operational dynamics await full characterization, with exons I-II orchestrating the signal peptide whereas exon VIII governs membrane-proximal electrostatic determinants [37]. The highly conserved KIEELE motif in the intracellular region, with no homology to other known proteins, mainly enables LAG-3 to suppress T-cell activation and proliferation [38]. Studies indicate that mutating KIEELE leads to the loss of the LAG-3 receptor's negative regulatory function, thereby promoting T-cell proliferation and activity. The intracellular region also includes the glutamate-proline repeat sequence (EP sequence), closely related to its signal-transduction function. These two domains, linked by a transmembrane scaffold protein, exhibit structural homology to the CD4 co-receptor and engage its canonical ligand, MHCII molecules. However, LAG-3 uses an additional 30-amino-acid loop in D1 to bind to MHCII with higher affinity [30,39,40]. LAG-3 primarily binds to MHC-II, delivering inhibitory signals through its cytoplasmic domain to suppress CD4+ T-cell activation and facilitate tumor immune escape [41].(Fig. 1.b)

However, studies reveal that MHC-II binding is dispensable for LAG-3-mediated immunosuppression. Beyond MHC-II, LAG-3 interacts with alternative ligands, such as galectin-3, LSECtin, and FGL1, and FGL1, suggesting multifaceted roles in immune regulation.

Ligands of LAG-3

Galectin-3

Galectin-3 (31 kDa), a β-galactoside-binding lectin, modulates T-cell responses via immunoregulatory mechanisms [42]. Specifically, its interaction with the D1 and D2 domains of LAG-3 induces conformational changes in the receptor, enhancing affinity for the intracellular KIEELE motif. Subsequently, LAG-3 dimerization recruits downstream effectors, including the tyrosine phosphatase SHP-1 and the ectonucleotidase CD39 [43,44]. Mechanistically, SHP-1 dampens TCR signaling by dephosphorylating pivotal kinases, thereby suppressing T-cell proliferation [45], while CD39 hydrolyzes extracellular ATP/ADP to adenosine, impairing T-cell metabolism [46].(Fig. 1.b) Cytokines including IL-2, IL-4, and IL-7 significantly enhance Galectin-3 expression levels in activated T cells, establishing a feedback loop that amplifies immunosuppression [47,48]. Therapeutically, disrupting the LAG-3/Galectin-3 axis restores antitumor immunity.

Liver Sinusoidal Endothelial Cell Lectin

LSECtin, a C-type lectin receptor belonging to the DC-SIGN subfamily [49], is localized to dendritic and tumor cells, where it engages LAG-3 to inhibit antitumor T-cell activity [50].(Fig. 1.b) In melanoma, LSECtin overexpression correlates with tumor progression and diminished tumor-infiltrating lymphocyte (TIL) responses [51,52]. Mechanistically, LSECtin downregulates cell-cycle kinases (CDK2, CDK4, CDK6) in effector T cells, arresting their proliferation. Additionally, this lectin promotes the motility and infiltration of gastric carcinoma cells, while LSECtin-blocking antibodies suppress these phenotypes. Clinically, LSECtin on liver sinusoidal endothelial cells facilitates colorectal cancer liver metastasis, highlighting its role in metastatic niche formation [52]. Notably, LSECtin interacts with the co-regulatory molecule LAG-3, and blocking LAG-3 can restore the secretion of IFN-γ, while melanoma-expressed LSECtin reduces the secretion of IFN-γ [53], indicating that LSECtin promotes tumor growth, and blocking the binding of LAG-3 to it can play an antitumor role.

Fibrinogen-like protein 1

FGL1, a fibrinogen-related protein, is categorized within the FREP family, exists as a 68-kDa homodimer stabilized by disulfide bonds [54]. Structural analyses reveal FGL1 is organized into two functional modules: an N-terminal α-helical coiled-coil domain (CCD) facilitating dimerization and a C-terminal fibrinogen-like domain (FD) responsible for high-affinity LAG-3 engagement [55,56]. From a functional standpoint, FGL1 demonstrates heightened expression on the surface of breast cancer cells and is intracellularly abundant in NSCLC cells. FGL1′s FD domain and LAG-3 D1/D2 domains form each binding interface [57].

Notably, FGL1 also acts as an acute-phase protein generated by hepatocytes in response to IL-6 and IL-22, and hepatocyte nuclear factor 1 (HNF1). Beyond its role in immunosuppression, unbound FGL1 may regulate processes such as liver regeneration and clot formation. Interestingly, proteins structurally related to FGL1, including angiopoietin, tenascin, and fibrinogen are implicated in angiogenesis, apoptosis, and extracellular matrix remodeling [[58], [59], [60], [61]], suggesting FGL1 may similarly influence these pathways. Clinically, FGL1 is overproduced by cancer cells, and elevated plasma FGL1 levels correlate with adverse clinical outcomes and refractoriness to PD-1 blockade [57].

At the molecular level, FGL1 facilitates tumor progression and metastatic dissemination via LAG-3 ligation on immune cells. Consequently, targeted disruption of the LAG-3/FGL1 interaction offers a viable therapeutic avenue to rejuvenate antitumor immune responses.(Fig. 1.b)

Molecular biological characteristics of TIM-3

TIM-3 (T-cell immunoglobulin and mucin domain-containing protein 3), a key immune checkpoint molecule within the TIM family, mediates immune checkpoint functions. Structurally, TIM family proteins feature an N-terminal IgV domain with five conserved atypical cysteine residues, a mucin-containing stalk, transmembrane domain, and intracellular cytoplasmic tail [62]. The IgV domain of TIM-3 engages four distinct ligands: galectin-9 [63], phosphatidylserine (PtdSer) [64], High-mobility group box 1 (HMGB1), which binds necrotic tumor-derived nucleic acids to activate dendritic cell-mediated innate immunity [65], and CEACAM1, an autologous T-cell ligand that suppresses T-cell activation [66].

It is worth noting that, TIM-3′s cytoplasmic tail lacks classical inhibitory motifs but contains five evolutionarily conserved tyrosine residues (Tyr256/263/272/276/279) shared across mammalian species. Tyr256/Tyr263 establish essential binding interfaces for BAT3 (HLA-B-associated transcript 3) and FYN kinase. During T-cell activation, TIM-3 translocates to lipid raft-enriched immunological synapses, co-localizing with BAT3 and LCK kinase [67]. In the unliganded state, BAT3 constitutively associates with TIM-3′s cytoplasmic tail, recruiting active LCK to maintain T-cell responsiveness. Ligand engagement (galectin-9/CEACAM1) induces ITK-mediated phosphorylation of Tyr256/263 [66,68].

This post-translational modification displaces BAT3 from TIM-3, unmasking its inhibitory potential. BAT3 deficiency upregulates co-inhibitory receptors and attenuates autoimmune pathogenicity, demonstrating BAT3-mediated feedforward inhibition [69]. FYN competes with BAT3 for TIM-3 cytoplasmic domain binding, suggesting its role in initiating inhibitory signaling cascades. Mechanistically, FYN initiates T-cell anergy through PAG phosphorylation in glycosphingolipid-rich microdomains, recruiting CSK to phosphorylate inhibitory residues on LCK, ultimately suppressing TCR signaling. TIM-3 further impairs T-cell function by interacting with CD45/CD148 phosphatases, destabilizing immunological synapse integrity [67].(Fig. 1.c)

Molecular biological characteristics of TIGIT

TIGIT, a checkpoint receptor belonging to the immunoglobulin superfamily with immunoreceptor tyrosine-based inhibitory motifs (ITIMs), demonstrates selective expression on lymphocytes and NK cells, including CD4+/CD8+ T cell subsets and Tregs. Quiescent lymphocytes exhibit minimal TIGIT expression, whereas activation induces significant TIGIT upregulation in these populations. Immunological profiling reveals Tregs, antigen-experienced T cells, and NK cells show maximal TIGIT density in unprimed murine models and immunocompetent human subjects [70,71]. TIGIT, a prominent therapeutic target in immuno-oncology, engages CD155 on antigen-presenting or neoplastic cells, suppressing cytolytic functions in T lymphocytes and NK cells.

TIGIT, structurally classified within the rapidly expanding poliovirus receptor (PVR)-related protein family, represents a distinct member of this group [70,72]. Structurally defined by an IgV extracellular region, a type I transmembrane domain paired with a cytoplasmic compartment containing an inhibitory tyrosine-based immunoreceptor motif (ITIM) and a structural homolog of the immunoglobulin tyrosine tail (ITT) sequence [70,71,73]. This receptor operates within a multi-component regulatory axis comprising inhibitory partners (CD96/Tactile, PVRIG/CD112R), the co-stimulatory competitor CD226/DNAM-1, and ligand networks featuring CD155 (PVR/NECL-5) and CD112 (Nectin-2/PVRL2) [70,[74], [75], [76], [77], [78]]. Mirroring the CD28/CTLA-4/CD80/CD86 co-stimulatory axis, TIGIT and DNAM-1 immune checkpoint molecules engage in ligand competition to modulate immune activation-suppression equilibrium [72]. Within the tumor microenvironment, TIGIT mediates immunosuppression through five core mechanisms: direct T cell inhibition via CD155 engagement-induced signaling cascades; APC-mediated indirect suppression through IL-10 induction and IL-12 suppression; competitive CD155 binding with higher affinity than CD226, impairing CD226 dimerization-dependent activation; potentiation of Treg immunosuppressive capacity; Fap2 protein-mediated enhancement from Fusobacterium nucleatum through TIGIT ligation [[79], [80], [81], [82]].(Fig. 1.d)

TIGIT intrinsically mediates cell-autonomous suppression. Agonist antibodies targeting this receptor inhibit TCR signaling cascades, thereby attenuating T-cell clonal expansion and effector responses [71,83,84]. TIGIT attenuates NK cell degranulation capacity, secretory function, and anti-CD155⁺ tumor cytotoxicity in murine/human systems [80,81,84]. TIGIT-driven interaction between NK cells and CD155+ MDSCs inhibits ZAP70/Syk-ERK1/2 phosphorylation, consequently diminishing NK cell cytotoxic capacity [85], thereby attenuating tumor suppression. Given its pan-lymphocytic expression profile, TIGIT constitutes a pivotal immune checkpoint that disrupts sequential phases of the cancer-immunity cycle [86]. In addition to effector cell populations, elevated TIGIT expression is prominently observed in regulatory immune cells, where it amplifies their immunosuppressive activity. In CD4+Foxp3−IL-10+ Tr1 cells, TIGIT expression directly correlates with the production of immunoregulatory IL-10 [87].(Fig. 1.d)

TIGIT acts as a Foxp3-regulated transcriptional target and is chiefly localized to CD4+Foxp3+ Treg populations [88,89]. TIGIT-positive regulatory T cells demonstrate upregulated canonical markers (Foxp3/CD25/CTLA-4) coupled with intensified TSDR demethylation, enhancing cellular stability [88,90]. Notably, CD226+ Tregs exhibit correlations with lineage instability and diminished suppressive function, exhibiting a distinct contrast to the TIGIT-expressing Treg subset [90]. Mechanistically, TIGIT signaling in Tregs directly upregulates inhibitory mediators such as IL-10 and fibrinogen-like protein 2 (Fgl2), reinforcing their immunosuppressive phenotype [88].(Fig. 1.d)

Immune checkpoint mechanisms in B-Cell lymphoma microenvironment

The PD-1/PD-L1 pathway critically contributes to immune evasion mechanisms by modulating T-cell responses [91,92]. In the immune microenvironment of B-cell lymphoma, tumor cells frequently exhibit high-level expression of PD-L1. Following PD-1 engagement at T-cell membranes, this interaction attenuates T-cell responsiveness by reducing activation signals, hindering clonal expansion, and limiting cytokine production. Compromised T cell-mediated cytotoxicity facilitates tumor immune evasion by impairing immunological surveillance and clearance mechanisms [92]. Although immune checkpoint inhibitors exemplified by anti-PD-1/PD-L1 mAbs are now widely utilized in managing multiple malignancies, including certain B-cell lymphomas, and have notably improved the survival rate of some patients, they demonstrate constrained therapeutic efficacy confined to specific patient subpopulations. Moreover, a significant number of patients eventually develop drug resistance [93].

Recent studies have shown that in the immune microenvironment of B-cell lymphoma, LAG-3 demonstrates high-affinity engagement with MHC class II molecules. This interaction disrupts T-cell receptor signal transduction, inhibits the activity and proliferation of T cells, and can also modulate the metabolic state of T cells, promoting T-cell exhaustion and diminishing the body's immune response to B-cell lymphoma [94,95]. Currently, research on LAG-3 inhibitors is in progress. Blocking the LAG-3 pathway restores T-cell activity and enhances antitumor immunity.

TIM-3 is a co-inhibitory receptor family member [96,97]. TIM-3 inhibition may reverse PD-1/PD-L1 therapy resistance [98]. Immune checkpoint molecules cooperatively engage within B-cell lymphoma's tumor immune niche. co-regulating immune cell activities and modulating tumor onset, progression, and therapeutic efficacy. Elucidating their functional mechanisms will advance enhanced immunotherapy design against B-cell lymphoma. TIGIT demonstrates predominant membrane localization in T lymphocytes and natural killer cells [99]. Within the immunological niche of B-cell lymphoma, upon binding to ligands such as poliovirus receptor (PVR), TIGIT suppresses T lymphocyte and natural killer cell activation, attenuates cytokine secretion, and compromises antitumor cytotoxicity. TIGIT further indirectly shapes the immune milieu by modulating regulatory T cell (Treg) functionality [100]. Recent research papers have disclosed that Tiragolumab, an anti-TIGIT monoclonal antibody, enhances Atezolizumab (anti-PD-L1 mAb) efficacy in lung cancer via macrophage or Treg modulation within the tumor microenvironment. Although the research subject is lung cancer, it provides crucial insights into TIGIT's mechanisms within the tumor immune microenvironment [93].

PD-1/USP5 regulatory mechanisms and LAG-3 gene blockade strategies

In summary, our findings highlight the emerging role of immune checkpoint modulation in B-cell lymphoma therapy. However, our understanding of immune checkpoints remains incomplete. With further in-depth exploration, recent research advancements focusing on the PD-1 and LAG-3 immune checkpoints will provide novel strategies for future lymphoma therapies. While studies involving TIM-3 and TIGIT have yet to yield conclusive results, we believe that future research in these areas will also inform clinical treatment strategies.

USP5 stabilizes PD-1 through deubiquitination and synergizes with the ERK signaling pathway to promote tumor immune escape

Interaction between USP5 and PD-1: Recently, new research has achieved a breakthrough in the field of PD-1 regulation and tumor immunotherapy. Their findings offer a novel perspective for a deeper understanding of the mechanism of action of PD-1 inhibitors in previously untreated B-cell lymphoma. Through two advanced technical approaches, immunoprecipitation and mass spectrometry analysis, the research uncovered a specific interaction between ubiquitin-specific protease 5 (USP5) and PD-1 [101]. In the process of post-translational modification of proteins, ubiquitination and deubiquitination play crucial regulatory roles, jointly maintaining protein stability and various physiological processes within the cell. As a deubiquitinating enzyme, USP5 plays an essential role in this process [102]. This study demonstrates that USP5 specifically deubiquitinates PD-1 by stripping polyubiquitin chains, stabilizing PD-1 in cellular contexts. In tumors, this USP5-PD-1 axis elevates PD-1 protein levels, sustaining its immunosuppressive activity to facilitate tumor immune evasion. ERK-driven Thr234 phosphorylation on PD-1 promotes USP5-PD-1 association. As a central signaling pathway, ERK governs proliferation, differentiation, and apoptotic processes [103,104]. The study findings indicate that ERK critically regulates PD-1 expression through post-translational modification mechanisms. Experimental evidence shows that ERK-dependent phosphorylation at the Thr234 residue of PD-1 enhances its binding affinity for ubiquitin-specific protease 5 (USP5). This specific molecular interaction facilitates PD-1 deubiquitination, thereby increasing its protein stability through reduced proteasomal degradation, ultimately exerting a substantial impact on tumor immunity. Within tumor microenvironments, dysregulated ERK signaling may amplify PD-1-mediated immunosuppression, thereby facilitating tumor immune evasion through these molecular mechanisms.

To probe USP5′s role in tumor immunity, a recent study generated Usp5 conditional knockout (cKO) mice via genetic ablation. After conditionally knocking out Usp5 in T cells, a series of anti-tumor experiments were conducted on Usp5 cKO mice and wild-type (WT) mice. The results indicated that Usp5 cKO mice exhibited a more potent anti-tumor effect than WT mice. In MC38 cells co-cultured with USP5-deficient cells, apoptosis was significantly increased. USP5 deletion enhances CD8⁺ T cell-dependent elimination of MC38 tumors. Usp5 cKO mice exhibited markedly reduced tumor progression compared to WT controls, likely linked to diminished PD-1 stability from USP5 loss, which boosts T-cell activation and proliferation, improving tumor cell targeting. T cells from cKO mice showed heightened secretion of antitumor cytokines (e.g., IFN-γ, TNF-α) and enhanced proliferative capacity, enabling robust clonal expansion within tumors. Consistently, PD-1 levels in cKO T cells were significantly reduced, underscoring USP5′s critical role in PD-1 stabilization. Lower PD-1 expression alleviates T-cell suppression, synergistically amplifying antitumor immunity. These findings establish USP5 as a driver of tumor immune evasion via PD-1 regulation, proposing USP5 inhibition as a strategy to potentiate T-cell-mediated tumor clearance and improve immunotherapy outcomes [101].

Anti-PD-1 therapy selectively depletes CD8⁺ Trm, CD4⁺ Tregs, IL1B⁺ monocytes, and CCL2⁺ fibroblasts while enriching CD8⁺ Tem, CD4⁺ Th, CD20⁺ B cells, and HLA-DRA⁺ endothelia. Tumor-associated inflammation perpetuates residual malignancy via immunosuppressive crosstalk with cytotoxic T cells and interconnected immune populations. These dynamics collectively delineate mechanistic insights into ICI success while highlighting actionable targets to overcome therapeutic resistance [105].

Mechanisms and therapeutic applications of synergistically enhanced anti-tumor immune responses via LAG-3-targeted bispecific antibodies and CRISPR gene-editing technology

In recent years, treatment strategies targeting LAG-3 have not been confined to monoclonal antibodies. Remarkable progress has also been made in the research of bispecific antibodies and gene-editing technologies. These emerging technologies offer new possibilities for enhancing the anti-tumor immune response.

Bispecific antibodies (BsAbs), engineered to concurrently target two antigens, are increasingly explored in cancer immunotherapy. BsAbs directed against LAG-3 mediate dual checkpoint blockade (LAG-3/PD-1), synergistically amplifying T-cell reinvigoration and antitumor immunity [106,107]. A bispecific LAG-3 and PD-1 antibody exhibits robust antitumor activity in preclinical models. Studies demonstrate that this dual-targeting antibody concurrently antagonizes LAG-3 and PD-1 signaling axes, markedly boosting T-cell, and demonstrating a superior therapeutic effect compared to single antibodies in various tumor models [107]. In murine melanoma and colorectal cancer models, the LAG-3/PD-1 bispecific antibody achieved synergistic tumor control and prolonged survival, concomitant with activation of tumor-infiltrating T cells and augmented antitumor immunity within the tumor niche [108].

CRISPR-Cas9 editing represents a transformative tool in tumor immunotherapy, enabling genetic reprogramming of T cells to augment antitumor function. Targeted LAG-3 ablation disrupts its immunosuppressive signaling, thereby potentiating T-cell-mediated tumor clearance [109]. CRISPR-Cas9-mediated LAG-3 disruption in T cells enhances their antitumor efficacy in preclinical models [114]. LAG-3-deficient T cells exhibited augmented proliferation and cytotoxicity, driving potent tumor clearance. In murine melanoma and lung cancer models, these cells curbed tumor growth and prolonged survival [110].

LAG-3-deficient T cells exhibited enhanced proliferation and cytotoxicity, driving robust tumor elimination. In murine melanoma and lung cancer models, these cells suppressed tumor progression and extended survival [109,110]. Knocking out LAG-3 eliminates its inhibitory effect on T cells, enabling T cells to more effectively recognize and kill tumor cells. Engineered T cells demonstrate prolonged persistence and functional durability in tumor microenvironments, advancing novel T-cell immunotherapy strategies [111].

In summary, the further advancement of basic research has provided novel approaches for exploring immunotherapy targeting immune checkpoints in lymphoma. Currently, several immune checkpoint inhibitors have entered clinical trials, offering new hope for lymphoma patients. Detailed therapeutic efficacy and safety profiles of these agents are presented in Table 1, Table 2.

Table 1.

Efficacy and safety of immune checkpoint inhibitor monotherapy.

Name	Inhibitor	Phase	Efficacy (ORR, OS, PFS)	Safety
Pembrolizumab	PD - 1 Inhibitor	Phase I, IB, II	In a Phase 1B study of 10 relapsed or refractory primary mediastinal B - cell lymphoma patients, the ORR was 40 %.	Hypothyroidism, diarrhea, nausea and pneumonia, Fatigue, edema, weight loss and joint pain
			In a Phase 2 trial of 84 high - risk cHL patients, the ORR was 99 %,
			In a Phase 2 trial of 31 recurrent/resistant classical Hodgkin's lymphoma cases (median observation period: 9.7 months), the ORR reached 64 % (SD:23 %, CR:16 %, PR:48 %).
Nivolumab	PD - 1 Inhibitor	Phase II	In a Phase 2 trial of untreated myelodysplastic syndrome, the best ORR of PD - 1 monotherapy was 27 % (3/11)
Tislelizumab	PD - 1 Inhibitor	Phase II	In a study of 249 advanced HCC patients, with a median follow - up of 12.7 months, the ORR was 13 %,	Elevation of liver transaminases
			In a Phase 2 study of 39 CNS - relapsed/refractory primary DLBCL patients, the ORR was 70.8 % and the CR rate was 41.7 %,
			In a retrospective study of 11 relapsed or refractory Hodgkin lymphoma patients, the ORR was 90.9 %, the CR rate was 36.4 %, the estimated 3 - year PFS was 81.8 % and the 3 - year OS was 100.0 %
Cetrelimab	PD - 1 Inhibitor	Phase I/II	In a Phase I/II study of 192 advanced or refractory solid - tumor patients, 2 patients achieved complete response (CR), 22 achieved partial response (PR), and half achieved stable disease (SD) or better.	Well tolerated
Relatlimab (BMS - 986016)	LAG - 3 Inhibitor	Phase Ⅲ
Favezelimab (MK - 4280)	LAG - 3 Inhibitor		Clinical trial for advanced colon cancer	Fatigue, nausea
ML - T7	TIM-3 Inhibitor
Sabatolimab	TIM-3 Inhibitor	Phase II	In a Phase 2 study of 10 LR - MDS patients with cytopenia, the ORR was 33.3 %	Anemia, neutropenia, myocardial infarction, central line catheter infection, pneumonia, thrombocytopenia, rash and hypoxia
Ociperlimab	TIGIT Inhibitor	Phase I	In a Phase 1 study of 32 advanced/metastatic solid - tumor patients, PR was 10.0 %, SD was 40.0 %, and disease progression was 43.3 %	Well - tolerated
ZGGS15	TIGIT and LAG - 3 Bispecific Antibody

Table 2.

Efficacy and safety of combination therapies.

Name	Inhibitor	Phase	Efficacy (ORR, OS, PFS)	Safety
Pembrolizumab + Nivolumab	Combination of PD - 1 Inhibitors	Phase I	In 23 patients with refractory Hodgkin lymphoma, the ORR was 87 % and CR was 17 %.	Toxicity was manageable.
Aza - ipi - nivo (Azacitidine - Ipilimumab - Nivolumab)	Combination of PD - 1 Inhibitors	Phase II	In 66 patients with untreated myelodysplastic syndrome, the CRc was 46 %.
Aza - ipi (Azacitidine - Ipilimumab)	Combination of PD - 1 Inhibitors.	Phase II	In 66 patients with untreated myelodysplastic syndrome, the CRc was 13.3 %.
Aza - nivo (Azacitidine - Nivolumab)	Combination of PD - 1 Inhibitors.	Phase II	In 66 patients with untreated myelodysplastic syndrome, the CRc was 40 %.
Ipi + Nivolumab (Ipilimumab + Nivolumab)	Combination of PD - 1 Inhibitors	Phase II	In 13 patients with classical Hodgkin lymphoma who progressed after PD - 1 blockade, the ORR was 50 %.
Tislelizumab + pemetrexed	Combination of PD - 1 Inhibitors	Phase II	In 39 patients with CNS - relapsed/refractory primary diffuse large B - cell lymphoma, the ORR was 70.8 % and the CR rate was 41.7 %.	Rash and Fatigue
Relatlimab + Nivolumab (BMS - 986016 + Nivolumab)	Combination of LAG - 3 Inhibitor and PD - 1 Inhibitor	Phase Ⅲ	Patients with treatment-naive advanced melanoma showed significantly prolonged PFS with combination therapy versus nivolumab monotherapy (median 10.1 vs. 4.6 months; HR 0.75, 95 % CI 0.6-0.9, p = 0.0055).
Favezelimab + Pembrolizumab (MK - 4280 + Pembrolizumab)	Combination of LAG - 3 Inhibitor and PD - 1 Inhibitor	Clinical trial for advanced colon cancer	Overall outcomes showed 6.3 % ORR with 10.6-month median DoR, 8.3-month OS, and 2.1-month PFS. In PD-L1 CPS≥1 subgroups, exploratory data revealed 11.1 % ORR, 12.7-month OS, and 2.2-month PFS.	Fatigue
Ociperlimab + Tislelizumab	Combination of TIGIT Inhibitor and PD - 1 Inhibitor	Phase I	In 32 patients with advanced/metastatic solid tumors, PR was 10.0 %, SD was 40.0 %, and disease progression was 43.3 %.	Well - tolerated
ZGGS15 + Nivolumab	Combination of TIGIT and LAG - 3 Bispecific Antibody and PD - 1 Inhibitor		On the 18th day after treatment, compared with the vehicle group, the treatment of ZSAB015 plus nivolumab showed a significant tumor growth inhibition (TGI) of 95.80 % (p = 0.001).

Clinical advances in immune checkpoint inhibitors: efficacy and combination strategies of PD-1, LAG-3, TIM-3, and TIGIT-targeted therapies

The current primary clinical regimens for lymphoma treatment include R-CHOP and CAR-T therapy. Among these, R-CHOP remains the cornerstone frontline therapy for B-cell non-Hodgkin lymphoma (NHL), particularly pivotal in diffuse large B-cell lymphoma (DLBCL) management. Global trials confirm ∼50-70 % of DLBCL patients attain durable remission/cure with R-CHOP [112,113]. However, limitations such as treatment failure and relapse risk, immunosuppressive effects and cardiovascular toxicity, and insufficient guidance by molecular subtyping remain critical challenges restricting its broader clinical application [[114], [115], [116], [117]]. CAR-T therapy has achieved transformative progress in B-cell lymphoma management, demonstrating exceptional efficacy against relapsed/refractory DLBCL and follicular lymphoma [118]. The global phase III ZUMA-7 trial confirmed that CD19-targeted CAR-T therapies like axicabtagene ciloleucel as second-line treatment significantly improved the 4-year overall survival rate to 54.6 % and achieved a complete response rate of 60 % in patients with primary refractory or early relapsed DLBCL, outperforming conventional chemotherapy combined with autologous stem cell transplantation [119,120].

However, CAR-T therapy still faces multiple challenges, including critical issues such as toxicity management [121] and antigen escape phenomena [122], which cannot be overlooked. Furthermore, infection risks associated with long-term B-cell depletion and prohibitive treatment costs remain barriers to widespread clinical adoption [123]. Concurrently, immune checkpoint inhibitor innovations are methodically bridging these therapeutic deficiencies.

Immune checkpoint blockers exhibit marked therapeutic promise in lymphoproliferative malignancies, notably agents directed against PD-1, LAG-3, TIM-3, and TIGIT pathways. Clinical studies on monotherapies and combination therapies have achieved continuous breakthroughs. Current clinical strategies and their efficacy highlight the evolving landscape of ICIs, offering novel therapeutic approaches for lymphoma

PD-1 Inhibitors

Pembrolizumab

Pembrolizumab is a human-engineered IgG4κ monoclonal antibody designed to block PD-1. Unlike conventional antibodies, it lacks Fcγ receptor binding and complement activation, minimizing off-target cytotoxicity. Mechanistically, pembrolizumab inhibits PD-1/PD-L1 binding to reactivate T-cell-driven antitumor immunity. Phase I trial: Combined with nivolumab in 23 refractory Hodgkin lymphoma (HL) patients, it achieved an 87 % objective response rate (ORR) with manageable toxicity. Phase IB trial: In relapsed/refractory primary mediastinal B-cell lymphoma (n = 10), a 40 % ORR was observed among 9 evaluable patients. Phase II trials: For high-risk classical HL (n = 84), ORR reached 99 %, in relapsed/refractory HL (n = 31), ORR was 64 % at 9.7-month follow-up [[124], [125], [126], [127], [128], [129], [130]].

Nivolumab

Nivolumab, a humanized IgG4 monoclonal antibody, binds specifically to the PD-1 receptor [16,131]. By blocking PD-1/PD-L1 binding, it alleviates tumor-cell-mediated T-cell inhibition and enhances anti-tumor effects through T-cell apoptosis induction and tumor microenvironment inhibition.

In a phase 2 trial of untreated myelodysplastic syndrome with 66 patients divided into three cohorts, the complete remission with incomplete hematologic recovery (CRc) varied: 13.3 % for the aza-ipi group, 40 % for the aza-nivo group, and 46 % for the aza-ipi-nivo group [132]. In a phase 2 trial of 13 classical Hodgkin lymphoma patients who progressed after PD-1 blockade and were treated with ipilimumab, PD-1 monotherapy had a 27 % best ORR, while the ipi + nivolumab combination had a 50 % ORR [133]. Tumor mutational burden (TMB) serves as an extensively validated biomarker for predicting therapeutic response to PD-1/CTLA-4 inhibitor-based immunotherapy. This approach measures tumor DNA mutation burden and demonstrates association with clinical response, as evidenced in nivolumab-treated lung cancer cohorts [134,135].

Tislelizumab

Tislelizumab, a PD-1 inhibitor designed to limit Fcγ receptor binding on macrophages, shows promise in solid-tumor treatment [[136], [137], [138], [139], [140], [141], [142]]. In a 249-patient study of advanced hepatocellular carcinoma (HCC), after 12.7-month follow-up, the ORR was 13 % with 15 % reporting grade ≥ 3 treatment-related AEs. It had durable responses and good tolerance [143]. For central nervous system-relapsed/refractory primary diffuse large B-cell lymphoma (DLBCL), a phase 2 study with 39 patients using tislelizumab + pemetrexed had an ORR of 70.8 % and a 41.7 % complete remission (CR) rate. Rash and fatigue were common treatment-related adverse events (TEAEs) [144]. A cohort of 11 R/R HL patients receiving multimodal regimens with ASCT achieved 85 % ORR, 3-year PFS/OS rates of 72 %/89 %, with predominantly grade 1-2 toxicities during induction phase [145].

Cetrelimab

Cetrelimab, a human-derived IgG4κ monoclonal antibody targeting PD-1, inhibits the PD-1/PD-L1 interaction, activating T cells for enhanced anti-tumor killing and seeing clinical application [[146], [147], [148]]. In a phase I/II trial involving 192 patients with advanced/refractory solid tumors, it was well-tolerated with good anti-tumor activity (2 complete remissions, 22 partial remissions, ∼50 % stable disease or better) [146]. PD-L1 blockade demonstrates superior progression-free survival (PFS), overall survival (OS), and tolerability. Yet monotherapy shows limited efficacy against tumor immune evasion, with response rates reaching only 13 % in eligible cohorts and ORR below 30 % across solid tumors [149,150]. Thus, combination therapy is common in lymphoma treatment, and the full potential of PD-1 inhibitors requires further exploration.

Clinical application of LAG-3 inhibitors

LAG-3-targeting mAbs reprogram immune landscapes via curbing IL-12/IFN-γ secretion, disrupting MHC-II-driven monocyte activation, and impairing IL-12-dependent T-cell priming [151].

Relatlimab (BMS-986016)

This humanized IgG4 mAb (e.g., relatlimab) engages LAG-3 with high affinity, preventing MHC-II engagement to reinvigorate exhausted T cells, thereby bolstering antileukemic immunity and cytokine release. However, it also inhibits T-cell and NK-cell activation, reducing pathogen clearance. It has anti-tumor and immunomodulatory effects. In a phase III study on advanced melanoma, the nivolumab combination therapy demonstrated significant PFS prolongation [152,153].

Favezelimab (MK-4280)

As a human-engineered IgG4 monoclonal antibody, it blocks LAG-3/MHC class II interaction, enhancing cytokine (IFN-γ, IL-2, IL-8, TNF-α) and chemokine (CCL4, CXCL10, CCL22) secretion in T cells [[154], [155], [156]]. In an advanced colon cancer clinical trial, a comparison was made between favezelimab monotherapy and its combination with pembrolizumab. Treatment-related adverse events (TRAEs) exhibited comparable incidence rates in both cohorts, with rates of 65 % in the monotherapy group and 65.2 % in the combination group. The incidence of grade 3 TRAEs was 15 % in the monotherapy group and 20 % in the combination group. Common TRAEs encompassed fatigue and nausea. The combination therapy demonstrated a verified objective response rate (ORR) of 6.3 %, exhibiting a median duration of response of 10.6 months. For tumors expressing PD-L1 combined positive score (CPS) ≥1, the ORR reached 11.1 % [157].

TIM-3 Inhibitors

ML-T7

ML-T7 is the most recent TIM-3 small-molecule inhibitor acting on Tim-3′s FG-CC0 cleavage site. TIM-3 engages phosphatidylserine (PtdSer) and CEACAM1, while ML-T7 potentiates survival, antitumor efficacy, and exhaustion resistance in CD8⁺ cytotoxic and CAR T lymphocytes across experimental models. Additionally, it promotes the cytotoxicity of natural killer (NK) cells and the antigen-presenting ability of dendritic cells (DCs), and enhances DC functions through interactions with Tim-3 and Tim-4. Intraperitoneal administration of ML-T7 suppresses tumor growth in a manner similar to Tim-3-blocking antibodies, thereby reducing tumor progression in mice [158].

Sabatolimab

Sabatolimab, an IgG4 antibody that targets the galectin-9 binding domain of TIM-3, was evaluated in a Phase 2 trial enrolling 10 low-risk myelodysplastic syndrome (LR-MDS) patients presenting with cytopenia. Only 1 patient experienced progressive disease, with the proportion of bone marrow blasts increasing from <5 % to 8 % by cycle 6. Adverse events of grade ≥ 3, such as anemia and neutropenia (affecting 5 patients each), were reported. The objective response rate was 33.3 %. Although the current focus is on LR-MDS, sabatolimab may be explored for the treatment of lymphoma in the future [159].

Clinically Studied TIGIT Inhibitors

Ociperlimab

Ociperlimab, a next-generation humanized mAb, selectively targets T-cell immunoreceptors through high-affinity TIGIT binding. However, the prognosis for advanced/metastatic solid-tumor patients remains poor. Nevertheless, the combination of ociperlimab and tislelizumab could potentially represent a new treatment option. In a phase I study involving 32 such patients, the combination was evaluated. The results showed a partial response (PR) rate of 10.0 %, a stable disease (SD) rate of 40.0 %, and a disease progression rate of 43.3 %. The combination regimen exhibited good tolerability and showed initial antitumor activity [149].

ZGGS15

ZGGS15 is a novel IgG4 bispecific antibody (BsAb) designed for cancer immunotherapy, targeting both TIGIT and LAG-3. It competitively blocks fundamental binding sites and activates T-cells more effectively than single-agent mAbs. When combined with nivolumab, it dose-dependently enhances T-cell activation, exhibits superior anti-tumor suppression, and shows a synergistic effect. By day 18 of treatment, it significantly inhibits tumor growth, suggesting its potential for lymphoma treatment [160].

Discussion

In summary, immune checkpoint inhibitors (ICIs) have demonstrated significant therapeutic potential in lymphoma, particularly agents targeting PD-1, LAG-3, TIM-3, and TIGIT. Breakthroughs in clinical studies of monotherapies and combination strategies continue to expand their applications, as shown in Table 1, Table 2.

PD-1 inhibitors: cornerstone of lymphoma therapy

PD-1 inhibitors remain pivotal in treating relapsed/refractory Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma (DLBCL). Pembrolizumab achieved an objective response rate (ORR) of 99 % in high-risk classical HL patients (n = 84) and 40 % in recurrent or resistant mediastinal primary B-cell lymphoma (Table 1). Nivolumab combined with ipilimumab in PD-1-resistant HL patients (n = 13) improved ORR to 50 %, significantly outperforming monotherapy (27 %) (Table 2). Tislelizumab paired with pemetrexed in relapsed central nervous system DLBCL (n = 39) yielded an ORR of 70.8 % and a complete response (CR) rate of 41.7 % with favorable tolerability (Table 2), underscoring the central role of PD-1 inhibitors in B-cell lymphomas.

LAG-3 inhibitors: synergistic agents in combination therapies

LAG-3 inhibitors enhance immune responses by blocking T-cell exhaustion signals. The dual checkpoint blockade of Relatlimab plus nivolumab markedly extended progression-free survival (PFS) in melanoma, supporting its evaluation in lymphoma combination regimens (Table 1). The bispecific antibody ZGGS15 (targeting LAG-3/TIGIT) synergizes with nivolumab to activate T cells, with preclinical studies showing marked tumor growth inhibition in lymphoma models (Table 2), highlighting its potential in refractory lymphomas.

TIM-3 and TIGIT inhibitors: emerging targets under exploration

The TIM-3 inhibitor ML-T7 enhanced CD8+ T-cell and CAR-T anti-tumor activity, significantly suppressing tumor progression in murine models (Table 1). Sabatolimab achieved a 33.3 % response rate in low-risk myelodysplastic syndromes (LR-MDS) and may potentially be extended to lymphoma (Table 1). For TIGIT, ociperlimab combined with tislelizumab showed a 10 % partial response (PR) rate in solid tumors (Table 2), while the bispecific antibody ZGGS15 (TIGIT/LAG-3) suppressed lymphoma tumor growth within 18 days in preclinical models, suggesting its utility as a backbone for combination regimens.

PD-1 inhibitors remain the cornerstone of lymphoma immunotherapy. Meanwhile, LAG-3, TIM-3, and TIGIT inhibitors—through combination strategies or bispecific antibody designs—hold promise to overcome drug resistance and broaden therapeutic indications, offering optimized solutions for refractory lymphomas.

Conclusion and future perspectives

As a highly heterogeneous hematological malignancy, the onset and progression of B-cell lymphoma are strongly linked to immune system dysregulation. While PD-1/PD-L1 blockade shows robust clinical responses in solid malignancies, sustained therapeutic efficacy persists exclusively within a limited patient cohort. Patients exhibiting initial therapeutic responses frequently manifest acquired resistance progression, necessitating mechanistic dissection of heterogeneous checkpoint inhibitor resistance pathways to devise targeted countermeasures.

In this review, we summarize the roles of various immune checkpoints in tumor immunity. However, understanding the mechanisms is only part of the equation, and the effects of inhibitors vary among individuals, which complicates the correct selection of treatment regimens and the design of strategies to overcome resistance. Current biomarkers demonstrate inconsistent predictive reliability for therapeutic responders, while mechanism-targeted modalities predominantly remain in preclinical development. Overcoming treatment resistance and achieving true personalized medicine remain critical challenges. Therefore, it is essential to discover more detailed resistance mechanisms, design more rational trials, and explore more appropriate biomarkers to guide precision medicine. PD-1 blockade elicits robust clinical responses in EBV-associated DLBCL and primary mediastinal B-cell lymphoma (PMBCL). The PD-1 inhibitor plus chidamide regimen demonstrates encouraging efficacy in NK/T-cell lymphoma. However, their response rates remain suboptimal in aggressive lymphomas such as conventional DLBCL. To address these limitations, advancements in combination therapies and emerging technologies are expected to play pivotal roles in overcoming therapeutic bottlenecks. This multi-dimensional approach is expected to develop optimized treatment strategies that will benefit patients with B-cell lymphoma.

CRediT authorship contribution statement

RuiXin Zheng: Visualization, Writing – original draft, Writing – review & editing. YuXiao Li: Visualization, Writing – original draft, Writing – review & editing. KaiXin Shi: Visualization, Writing – original draft, Writing – review & editing. YuanYuan Pan: Writing – review & editing. KaiYi Liu: Writing – original draft. JinCheng Song: Writing – review & editing. Li Li: Writing – review & editing.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.