The immune system is charged with maintaining a delicate equilibrium: strong enough to eliminate pathogens and tumors yet restrained enough to avoid excessive inflammation or autoimmunity. Achieving this balance requires the coordinated activity of regulatory cell populations, with Bregs and Tregs working in tandem through complementary suppressive mechanisms. Whereas Tregs are well defined by their lineage marker FOXP3, the pathways governing Breg function remain less well characterized, though emerging evidence has established their critical role in restraining pathogenic T cell activity.

Regulators of Bregs Function

Bregs primarily exert suppression through cytokine secretion, with IL-10 as the dominant mediator, supported by IL-35 and TGF-ꞵ. These cytokines converge to inhibit Th1 and Th17 differentiation and proliferation, thereby dampening pro-inflammatory responses (Fig. 2). Among these mediators, IL-10 is considered the hallmark of Breg activity, and its expression is tightly controlled by transcriptional and epigenetic mechanisms tightly control its expression.

Blimp-1

A central regulator of IL-10 in Bregs is Blimp-1 (B lymphocyte-induced maturation protein 1, encoded by Prdm1). Blimp-1 orchestrates the differentiation of B cells into plasmablast-like Bregs that produce IL-10. The plasmablasts (CD138+) are a subset of the IL-10-producing Breg cells during autoimmune inflammation [43]. Additionally, Blimp-1 serves as a key transcriptional regulator of plasmablast differentiation [44]. We believe that the research gap concerning different Breg subtypes, especially regulatory B cells from various B cell subsets, remains to be fully explored. Functional studies have shown that IL-10-producing B10 cells (CD19+CD1dhighCD5+) derived from Blimp-1 conditional knockout mice exhibit impaired suppression of naive CD4+ T cell proliferation, reflecting a loss of immunosuppressive capacity. Moreover, in Prdm1 knockout mice, the transition of Bregs into terminal IL-10-producing plasmablasts is disrupted. Interestingly, Blimp-1 plays a dual role. In resting B10 cells, IL-10 expression is reduced by Blimp-1, but in activated B10 cells, Blimp-1 enhances IL-10 production, emphasizing its context-dependent activity [45]. Blimp-1 is a non-redundant transcriptional regulator of Breg immunosuppression, with its absence tipping the balance toward pro-inflammatory cytokine production and autoimmune pathology (Fig. 2).

STAT3

Blimp-1 functions synergistically with STAT3 to regulate the Il10 promoter (Fig. 2). Upon immune activation, such as LPS stimulation, STAT3 binds directly to the Il10 promoter, but efficient transcription requires cooperation with Blimp-1. The DNA-binding domain of Blimp-1 is essential for enabling the phosphorylated STAT3 (Tyr705) to fully activate IL-10 expression in B10 cells. This interdependence shows that STAT3 alone cannot drive Il10 transcription, but with Blimp-1, it provides a potent transcriptional program for Breg-mediated suppression [45]. The importance of STAT3 in Bregs is further stressed by genetic studies. Within the literature, loss of STAT3 in B cells increases the severity of autoimmune uveitis, marked by reduced IL-10 and IL-35 levels [46].

Beyond IL-10, Blimp-1 also promotes the transcription of IL-35 by activating Il12a and Ebi3 through the BATF/IRF4/IRF8 axis [47]. Among the IL-35 subunits, IL-12p35 has shown strong immunoregulatory potential, suppressing Th17 proliferation and expanding Breg populations [48]. In addition, STAT3 regulates the expression of the inhibitory receptor LAG-3 on Bregs. In STAT3-deficient mice, diminished LAG-3 expression compromises the ability of LAG-3⁺ Bregs to suppress Th17 expansion, further illustrating STAT3’s central role in sustaining Breg immunoregulatory function [46]. While STAT3 clearly regulates IL-10, whether it directly drives IL-35 expression in Bregs remains unresolved. Nonetheless, IL-35 is functionally significant, as it induces the expansion of IL-10⁺ Bregs and CD5⁺CD19⁺B220lo Bregs, both of which suppress pathogenic T cell responses and ameliorate uveitis [8].

c-Maf

Another critical transcription factor, c-Maf, has also been shown to bind directly to the Il10 promoter upon LPS stimulation, thereby augmenting IL-10 production in Bregs [49]. Upstream regulators further refine this transcriptional network. IRF4 activates Prdm1 and induces Breg expansion, whereas IRF8 acts antagonistically, restraining this pathway (Fig. 2). The bifurcation of IRF4 and IRF8 activity thus determines the extent of Blimp-1 expression and downstream Breg differentiation [50].

HDAC

Epigenetic mechanisms superimpose additional layers of control. BACH2, a transcriptional repressor, directly suppresses Blimp-1 expression and limits plasma cell differentiation (Fig. 3). Human ChIP-seq data confirm that BACH2 binds the Il10 promoter and represses IL-10 production in B cells [51, 52]. Mechanistically, BACH2 recruits HDAC3 to the Prdm1 locus, driving deacetylation of H3K9 and silencing Blimp-1 transcription [53]. Although epigenetic programming of IL-10 competence is common, the recruitment of HDACs to chromatin upstream occurs in a context-specific manner. HDACs are epigenetic regulators of IL-10 expression in regulatory B cells. Inhibiting HDAC1 with Entinostat prevents it from binding to the nearby region of the IL-10 expression promoter in splenic B cells and IL-10-producing Bregs [54]. Additionally, inhibiting HDAC3 can promote the differentiation of plasma cells into CD138hiIL-10+IgM+ plasma cells [55], a distinct Breg subset, also regulated by epigenetic mechanisms, alongside the traditional Bregs (CD1dhi CD5+ (B10)). However, the identity of Bregs is not determined solely by surface markers; instead, they are epigenetically programmed, which modifies chromatin accessibility and influences IL-10 production in Bregs [56]. BACH2 typically binds to the IL-10 gene promoter, and genetic removal of BACH2 binds to the IL-10 gene promoter, and knocking out BACH2 genetically results in increased IL-10 production in IL-10-producing regulatory B cells [52]. Additionally, the BACH2-HDAC3 co-repressor complex epigenetically binds to the Blimp-1 locus [53]. These findings collectively support our model of BACH2-dependent repression of IL-10 expression via the Blimp-1 regulator.

PD-L1

PD-L1-mediated suppression represents another key mechanism (Fig. 2). PD-L1 (CD274) expressed on Bregs engages PD-1 (CD279) on T cells, directly inhibiting TCR signaling and reducing CD8⁺ T cell proliferation. Clinical studies in rheumatoid arthritis have shown that CD19⁺PD-L1⁺ Bregs are significantly reduced in untreated patients, while treatment restores their frequency and enhances T-cell suppression [57]. Myeloid-derived suppressor cells (MDSCs) also contribute to this pathway: MDSCs promote PD-L1 expression on Bregs, thereby enhancing their capacity to suppress CD8⁺ T cell proliferation. Notably, when PD-L1⁻ B cells are substituted in co-culture systems, this suppressive effect is lost, confirming the dependence of Breg-mediated suppression on PD-L1 [58].

Breg-mediated immunosuppression is a multilayered program integrating cytokine production, transcriptional and epigenetic regulation, and receptor-mediated signaling. IL-10 remains the central axis of this program, but its stabilization relies on the interactions of Blimp-1, STAT3, c-Maf, IRF4, and BACH2, as well as epigenetic modifiers such as HDACs (Figs. 2 and 3) Parallel pathways, including CD40-CD40L interactions and PD-L1 checkpoint signaling, expand the suppressive repertoire of Bregs (Fig. 2). Unlike Tregs, whose suppressive program is well established, Bregs represent a more fluid and plastic population, with their identity and function tightly controlled by the convergence of transcriptional networks and environmental cues.

Fig. 2The alternative text for this image may have been generated using AI.

Proposed mode of Transcriptional crosstalk between regulatory B and T cells causes IL-10-mediated immunosuppression in both cell types. Possible interaction between immune regulatory receptors/ligands on Bregs and Tregs. 2 A. Blimp-1-STAT3 mediates IL-10 activation and immunosuppression in Bregs. 2B. Blimp-1-mediated transcriptional activation of IL-10 leads to immunosuppression within the immune environment of Tregs. 2C. Co-stimulatory and checkpoint interactions of Breg-Treg mediate immunosuppressive crosstalk

Regulatory B cells enhance CD4 + regulatory T cell responses by secreting IL-10, primarily via an IL-10-dependent pathway that interacts directly with IL-10 receptors on CD4 T cells. Breg-derived IL-10 activates the STAT3 pathway, which promotes FOXP3 expression, turning T cells into more functional regulatory T cells and suppressing pro-inflammatory differentiation of Th17 and Th1 cells. Additionally, regulatory B cells produce TGF-beta, inducing FOXP3 transcription through SMAD2/3 in CD4 T cells. TGF-beta stimulates FOXP3 transcription and inhibits Th1/Th2 effector CD4+ T cell differentiation. The CTLA-4 on Tregs interacts with CD80 or CD86 on Bregs, enhancing Treg-mediated suppression. Moreover, Bregs’ expression of PD-L1 can bind to PD-1 on T cells, reducing PI3K/Akt/mTOR signaling and RORyt expression while increasing FoxP3 levels in Tregs. Overall, the epigenetic stabilization of the IL-10 locus in regulatory Bregs and the FOXP3 locus in Tregs underpins their crosstalk, although more research is necessary to understand the epigenetic profiles of Breg-Treg interactions.

Fig. 3The alternative text for this image may have been generated using AI.

Proposed model of Epigenetic regulation of IL-10-mediated immunosuppression by histone deacetylases (HDACs) in Bregs

Bregs in Autoimmune Disease

The immunosuppressive axis of the immune system is sustained through the coordinated activity of Tregs and Bregs, both of which serve to limit inflammation-associated tissue damage and preserve immune homeostasis (Fig. 4). By reinforcing self-tolerance, these regulatory populations counteract autoimmune pathology and restrain aberrant immune activation. This tolerance is achieved through multiple mechanisms, including the elimination of autoreactive lymphocytes, the secretion of suppressive cytokines such as IL-10, IL-35, and TGF-β, and the modulation of antigen-presenting cell (APC) activity. While Tregs primarily exert their effects by directly suppressing effector T cell responses, Bregs function as versatile immune modulators, shaping both innate and adaptive pathways to maintain balance within the immune system.

Multiple Sclerosis (MS)

Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system (CNS), defined by immune-mediated demyelination and progressive neurodegeneration. Disease pathology is orchestrated by autoreactive T helper subsets, particularly Th1 and Th17 cells, which establish an inflammatory cascade that drives both tissue injury and clinical progression [59].

Regulatory B cells play a central role in mitigating this pathology. B cell-derived IL-10 has been shown to reduce the severity of Th1-driven experimental autoimmune encephalomyelitis (EAE), the murine model of MS53. Within this context, CD40 signaling is required to induce IL-10 production in Bregs upon antigen encounter, demonstrating the importance of co-stimulatory pathways in shaping the suppressive phenotype of B cells [60]. Conversely, loss of CD40-CD40L signaling impairs Breg function in models of EAE and collagen-induced arthritis, underscoring its importance in autoimmune regulation [61]. The timing of regulatory activity also appears critical: B10 cells (CD1dhiCD5+IL-10+) exert their strongest anti-inflammatory effects during the early stages of EAE progression, whereas FOXP3+ Tregs predominantly regulate later phases of disease [62, 63].

In MS patients, however, these regulatory mechanisms are compromised. Although frequencies of CD4⁺CD25hi Tregs are not significantly altered compared with healthy controls, their suppressive capacity is diminished. Tregs isolated from MS patients fail to efficiently suppress effector T cells stimulated with recombinant myelin oligodendrocyte glycoprotein (MOG), demonstrating functional defects in antigen-specific tolerance [64]. Importantly, this impairment is observed across both relapsing and remission phases of disease, suggesting that Treg dysfunction is a persistent feature of MS rather than a state-specific defect. Consistent with this, Th17-mediated inflammation correlates with disease severity, and an inverse relationship between Tregs and Th17 cells has been reported [65].

Bregs, by contrast, show a more direct association with disease activity. Frequencies of IL-10⁺ Bregs positively correlate with MS severity [66]. However, their functional capacity appears compromised: in relapsing-remitting MS (RRMS), the differentiation of B cells into CD19⁺CD24hiCD38hi transitional Bregs is impaired, weakening their regulatory contribution. Notably, this dysfunction can be at least partially restored by treatment with the immunomodulatory peptide thymosin-α1 (T-α1), which enhances IL-10 production and re-establishes suppressive activity [67]. The push-and-pull between Tregs and Bregs in MS leads to deficiencies in both populations, which contribute to a permissive environment for Th1/Th17-driven neuroinflammation.

Systemic Lupus Erythematosus

The contribution of Bregs to the pathogenesis of systemic lupus erythematosus (SLE) remains incompletely defined, yet accumulating evidence points to both quantitative and functional defects in this population. Transitional Bregs (CD19⁺CD24hiCD38hi), typically a major source of IL-10, are reduced in frequency and display impaired IL-10 production in SLE patients [24]. These defects are particularly pronounced in individuals with lupus nephritis, where compromised Breg function correlates with loss of immunosuppressive control and enhanced disease activity [68]. Deficiencies in regulatory T cells add to this dysregulation. Circulating CD4⁺ Tregs are significantly reduced in SLE patients compared to both rheumatoid arthritis (RA) cohorts and healthy controls [69, 70]. Moreover, residual Tregs in SLE have impaired suppressive function, suggesting that failures across multiple regulatory cell compartments synergize to promote immune dysregulation.

The role of IL-10⁺ Bregs in lupus is also context-dependent. In lupus-prone mice, marginal zone Bregs appear early in disease, whereas plasmablasts and plasma cells dominate the IL-10-producing Breg compartment during active disease flares. Despite their expansion, these subsets exhibit functional impairment, as evidenced by elevated inflammatory gene signatures in lupus-prone MRL/lpr mice. This suggests that while Breg-like populations emerge during active disease, their regulatory function is blunted, allowing unchecked inflammation to persist [71]. Regulatory dysfunction in SLE extends beyond T cells to include both quantitative and qualitative defects in Bregs. Rather than restraining autoimmunity, impaired IL-10 production and context-dependent dysfunction may transform Bregs into insufficient or even maladaptive regulators of disease progression.

Inflammatory Bowel Disease (IBD)

Regulatory B cells also contribute to the control of intestinal inflammation, with B10 cells (CD1dhiCD5⁺IL-10⁺) emerging as a central subset. In dextran sulfate sodium (DSS)-induced models of colitis, B10 cells ameliorate intestinal injury, paralleling the protective effects observed in patients with ulcerative colitis [41]. Within the mesenteric lymph nodes (MLN), B cells demonstrate elevated CD1d expression, enhancing IL-10 production and reinforcing local immunoregulation. Interestingly, while enlarged MLNs have been reported in TCRα−/−, IL-2−/−, and IL-10−/− mice, CD1d upregulation was specifically observed in TCRα−/− and IL-deficient strains, suggesting that CD1d-driven Breg responses are engaged during inflammatory conditions [7]. Genetic models further reinforce the importance of B cells in intestinal homeostasis. TCRα−/− × Igµ−/− mice develop more severe spontaneous colitis than TCRα−/− mice alone, indicating that B cells exert a suppressive role rather than serving as initiators of intestinal inflammation [72]. Similarly, CD1d-deficient mice spontaneously develop intestinal inflammation, reinforcing the idea that Bregs, and particularly IL-10-producing B10 cells, are required to prevent uncontrolled mucosal immune activation [7, 72]. CD1d is a molecule that bridges Bregs and iNKT cells (invariant Natural Killer T cells) and helps stabilize the IL-10-producing Breg function. Its main role is to present lipid antigens. CD1d-mediated engagement of iNKT cells is necessary for maintaining and expanding functional Bregs, but CD1d alone does not support the intrinsic IL-10 transcription within Bregs.

Other Breg subsets also play protective roles in the gut. IL-33-responsive Bregs (BregIL−33) suppress the onset of spontaneous colitis in an IL-10-dependent manner, suggesting a link between epithelial alarmin signaling and the activation of suppressive B-cell networks that preserve mucosal immune tolerance [73]. In humans, frequencies of CD24hiCD38hi and CD5⁺ Bregs are significantly decreased in both peripheral blood and intestinal tissues of ulcerative colitis patients compared with healthy controls [74]. The reduction in this subset correlates inversely with disease severity, supporting a protective role for transitional-like Bregs in maintaining mucosal balance. Conversely, expansion of CD95⁺ Bregs has been associated with functional impairment, reflecting a skewing of Breg subsets toward a non-suppressive phenotype in inflammatory conditions [75]. Bregs are essential for maintaining intestinal immune homeostasis. Their impairment, whether by numerical reduction, altered signaling, or functional exhaustion, facilitates chronic inflammation and contributes to the pathogenesis of inflammatory bowel disease.

Rheumatoid Arthritis (RA)

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent joint inflammation, synovial hyperplasia, and progressive cartilage and bone destruction. Both innate and adaptive immune pathways contribute to disease pathology, with Th1- and Th17-driven responses playing a central role. Regulatory B cells, particularly IL-10-producing subsets, have been shown to counterbalance this inflammatory axis. Evidence from collagen-induced arthritis (CIA), a well-established murine model of RA, showcases that B cell-derived IL-10 is critical for controlling disease progression. In chimeric mice lacking IL-10−/− B cells, CIA severity is markedly increased, accompanied by amplified Th1 and Th17 responses, accentuating the non-redundant role of Bregs in restraining joint inflammation [76].

In human RA, several Breg subsets are numerically and functionally impaired. CD19⁺CD27⁺IL-10⁺ memory Bregs are reduced in frequency compared with healthy individuals, and their diminished regulatory capacity is reflected in a failure to suppress CD4⁺ T cell-derived IFN-γ production [77]. Similarly, the IL-10-producing B10 population, typically enriched within the transitional CD19+CD24hiCD27+ compartment, is significantly decreased in the peripheral blood of RA patients [78]. Checkpoint-regulated subsets are also affected. PD-L1⁺ Bregs, which normally suppress effector cytokine production, are reduced in RA and possess functional impairment. In particular, PD-L1⁺ B cells from RA patients fail to suppress IFN-γ and IL-21 secretion, further expanding upon defects in Breg-mediated regulation [38].

Impaired frequency and function of multiple Breg subsets, transitional, memory, and checkpoint-linked, contribute to the unchecked pro-inflammatory environment in RA. Loss of Breg-mediated regulation thus permits persistent Th1/Th17 activity, exacerbating joint inflammation and autoimmunity.

Type 1 Diabetes

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of pancreatic β cells, leading to insulin deficiency and lifelong dependence on exogenous insulin. Dysregulated immune tolerance plays a central role in disease onset, and emerging evidence implicates Breg deficiency in the failure to restrain autoreactive T cells. In patients with T1D, circulating transitional Bregs (CD24hiCD38hi) are significantly reduced in frequency compared with healthy controls [79]. Additional reductions in TIM-1⁺ Bregs and IL-10-producing Bregs have also been observed, suggesting a global defect across multiple Breg subsets [79].

Similarly, the frequency of IL-35⁺ Bregs, defined as CD19⁺CD24⁺CD40⁺CD38⁺ in humans, is diminished in peripheral blood mononuclear cells (PBMCs) of T1D patients. In the non-obese diabetic (NOD) mouse model, IL-35⁺ Bregs (CD19⁺CD1d⁺CD5⁺) are reduced in both the spleen and pancreatic draining lymph nodes, displaying a parallel impairment in murine autoimmune diabetes [80]. Mechanistic studies suggest that antigen-matured Bregs sustain tolerance by suppressing autoreactive T cells and supporting the survival and function of pancreatic β cells. In this way, Bregs may act as suppressors of inflammation and facilitators of β-cell preservation, offering a potential therapeutic axis for restoring endogenous insulin production in T1D [81].

Bregs in Cancer

In contrast to autoimmune diseases, where deficiencies in regulatory populations exacerbate inflammation, Tregs and Bregs in cancer act to create an immunosuppressive tumor microenvironment (TME) that favors immune evasion and tumor progression (Fig. 4). Within the TME, both regulatory cell types suppress antitumor immunity by limiting effector T cell activation and cytokine production, thereby enabling tumor cells to persist and proliferate.

The heterogeneity of regulatory B cell subsets complicates their characterization in cancer, but functional parallels with Tregs are evident. Both Tregs and Bregs converge on the production of immunosuppressive cytokines, including IL-10, IL-35, and TGF-β, and engage checkpoint pathways such as PD-1/PD-L1 to attenuate cytotoxic T lymphocyte activity. This overlap highlights a common immunoregulatory program, adapted in cancer to protect malignant rather than host tissues.

Breast Cancer

In breast cancer, regulatory B cells play a pivotal role in shaping a tolerogenic tumor microenvironment that facilitates metastasis and immune evasion. Mouse models using the 4T1 mammary carcinoma cell line, a highly metastatic model that closely mimics the biology of human triple-negative breast cancer, have revealed the emergence of a specialized subset termed tumor-evoked Bregs (tBregs). Unlike conventional IL-10-producing Bregs, tBregs exert their immunosuppressive function primarily through TGF-β, which reprograms naïve CD4⁺ T cells into FOXP3⁺ Tregs. This process expands the immunosuppressive compartment and promotes tumor progression and metastasis [82].

Beyond their role in Treg induction, Bregs within the breast cancer microenvironment actively secrete anti-inflammatory cytokines and suppress effector T cell responses, thereby reinforcing a state of immune tolerance that favors tumor outgrowth. Mechanistically, the generation of tBregs has been linked to lipid metabolism [83]. Specifically, the 5-lipoxygenase (5-LO)/FLAP/LT pathway and PPAR-α signaling have been implicated as critical regulators of Breg differentiation in breast cancer. Inhibition of these pathways disrupts tBreg development and breaks the Breg-driven immunosuppressive loop, punctuating their importance in sustaining tumor-promoting regulation [84].

Tregs likewise maintain a dominant immunosuppressive role in breast cancer, particularly within tumor-draining lymph nodes (TDLN). High accumulation and functional activation of FOXP3⁺ Tregs in these sites correlate with poor prognosis, demonstrating the cooperative nature of Breg- and Treg-mediated suppression in metastatic breast cancer [85]. In breast cancer, Bregs and Tregs do not act in isolation and form a synergistic immunoregulatory axis. Through both cytokine-mediated mechanisms and metabolic reprogramming, this axis establishes an immune-privileged niche that accelerates tumor progression and metastasis.

Colorectal Cancer

In colorectal cancer (CRC), regulatory B cells have been identified among tumor-infiltrating lymphocytes, where they contribute to the establishment of a tolerogenic microenvironment. A distinct subset of IL-10⁺ plasmablast-like Bregs, characterized by CD19loCD27hi expression, has been observed in resected CRC tissues. When co-cultured with peripheral blood CD3⁺ T cells, these CD19loCD27hi plasmablasts suppressed effector function, leading to reduced secretion of pro-inflammatory cytokines such as IFN-γ and TNF-α, in contrast to CD19hiCD27⁻ naïve B cells. These IL-10⁺ plasmablasts also expressed TIM-1 and IgG, but patients with colorectal tumors exhibited decreased frequencies of CD38⁺CD24⁺ transitional Bregs in peripheral blood, suggesting a systemic deficiency in immunoregulatory populations [86].

Additional insights into colitis-associated cancer (CAC), a subtype of CRC linked to chronic intestinal inflammation, further the relationship between Bregs, microbiota, and tumor progression. IgA⁺ plasma cells regulate CAC by shaping a tumor-protective microbial environment that dampens bacterial-driven inflammation. Concurrently, IL-10-producing Bregs restrain pathogenic Th1 and Th17 responses during chronic colitis, reducing the inflammatory signals that drive malignant transformation [87].

In CRC, Bregs operate both locally within the tumor and systemically to limit pro-inflammatory immunity. By curbing effector T cell responses and interacting with microbiota-dependent pathways, Bregs contribute to an immune landscape that paradoxically protects against excessive inflammation but also fosters tumor persistence and progression.

Hepatocellular Carcinoma (HCC)

In hepatocellular carcinoma (HCC), Bregs play a prominent role in dampening antitumor immunity and shaping an immunosuppressive tumor microenvironment. Experimental strategies have sought to disrupt these pathways. For example, an engineered CD19scFv-IL-10R fusion protein, designed to bind both CD19 and IL-10, was tested in murine models of HCC [88]. Treatment with this construct suppressed B10 Bregs and Tregs while preserving Th1 responses, leading to accumulation of IFN-γ-producing CD4⁺ T cells and cytotoxic CD8⁺ T cells that directly targeted tumor cells. The result was significantly reduced tumor growth, demonstrating the therapeutic potential of selectively interrupting Breg/Treg-mediated suppression [88].

Clinically, specific Breg subsets correlate with disease progression. A PD-1hi Breg population, characterized by CD5hiCD24hiCD27+CD38dim expression, has been linked to poor outcomes in HCC. These cells suppress T cell-mediated antitumor responses and thereby facilitate tumor persistence [89]. In addition, TIM-1⁺ Bregs, already implicated in other tumor settings, are enriched in HCC. TIM-1⁺ B cells are associated with reduced overall survival and worse prognosis compared with TIM-1⁻ counterparts, suggesting that TIM-1 may serve both as a functional marker of immunosuppressive Bregs and a prognostic biomarker in HCC [90]. In HCC, Bregs suppress cytotoxic immune surveillance through both checkpoint- and cytokine-driven mechanisms. Targeting these pathways, either by disrupting IL-10 signaling or by inhibiting PD-1⁺ and TIM-1⁺ Breg subsets, may represent a viable therapeutic strategy to restore effective antitumor immunity in liver cancer.

Melanoma

In melanoma, Bregs contribute directly to tumor progression by suppressing cytotoxic immunity and fostering a pro-tumorigenic microenvironment. Experimental studies using the B16F10 melanoma model demonstrated that B1a Bregs (CD1dintCD5⁺), which secrete IL-10, accelerate tumor growth when adoptively transferred into recipient mice. This effect was associated with impaired production of Th1 cytokines and diminished effector function in tumor-infiltrating CD8⁺ T cells, implicating IL-10 as a central mediator of Breg-driven suppression [17].

Beyond cytokine secretion, Bregs in melanoma also exploit signaling pathways that enhance tumor survival. CD5⁺ B cells have been shown to directly bind IL-6, initiating STAT3 activation, which in turn promotes tumor growth through transcriptional programs that support both immune suppression and tumor proliferation [91]. Clinical observations further reinforce the link between Bregs and melanoma progression. Circulating PD-L1⁺ Bregs are elevated in patients with advanced-stage melanoma (stages III-IV), with the highest frequencies observed in those with bone metastases compared to patients with primary tumors. This finding stresses the role of PD-1/PD-L1-mediated suppression in facilitating systemic immune escape during metastatic disease [37].

In addition, a distinct subset of IgG4⁺CD49b⁺CD73⁺ Bregs has been identified in melanoma, which promotes angiogenesis and tumor-associated vasculature. This population operates at the interface of immunoregulation and tumor remodeling, further broadening the spectrum of Breg-mediated mechanisms that sustain melanoma progression [92]. Bregs act as multifaceted contributors to melanoma progression, acting through IL-10-mediated suppression of effector T cells, IL-6/STAT3-driven pro-tumor signaling, checkpoint regulation, and the promotion of angiogenesis.

Pancreatic Cancer

In pancreatic cancer, regulatory B cells contribute to tumor initiation and progression by reinforcing an immunosuppressive environment during both early neoplasia and established disease. In vivo models of pancreatic tumorigenesis have identified an enrichment of CD19⁺CD1dhiCD5⁺IL-35⁺ B cells within early neoplastic lesions. These Bregs promote tumor growth, in part by driving immune tolerance, showcasing their role at the earliest stages of malignant transformation [93].

During chronic inflammation associated with pancreatic cancer, IL-35 expression is further upregulated. Mechanistically, the IL-35 subunit p35 (Il12a) is predominantly active in Bregs, whereas the Ebi3 subunit is strongly induced in CD4⁺ T cells, amplifying IL-35 signaling and contributing to pancreatic neoplasia [94]. Importantly, IL-35⁺ Bregs activate STAT3 through phosphorylation, providing a direct link between Breg-derived cytokines and tumor-promoting signaling cascades.

In pancreatic ductal adenocarcinoma (PDA), an increased frequency of CD19⁺CD24hi