Deeksha Sharma
Grace G. Bushnell2
Alexander P. Kalman- 1Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States
- 2Biomedical Engineering, University of Minnesota, Minneapolis, MN, United States
Bromodomain and Extra-Terminal domain (BET) proteins are key epigenetic readers that recognize and bind acetylated lysine residues on histones, orchestrating transcriptional programs that drive oncogenic processes. BET proteins regulate the expression of oncogenes involved in proliferation, survival, and differentiation, thereby promoting tumor initiation, progression, and therapy resistance across a wide range of solid tumors. Recent findings implicate BET proteins in maintaining cancer stem cells (CSCs), a subpopulation of tumor cells characterized with self-renewal capacity, plasticity, and the ability to evade conventional therapies. In CSCs, BET proteins coordinate stemness-associated transcriptional networks, and drive tumor persistence, metastasis, and relapse following treatment. BET proteins also shape the tumor immune microenvironment by modulating the expression of key immune checkpoint molecules such as PD-L1, regulating cytokine production, and controlling antigen presentation, which collectively influence adaptive and innate immune responses. BET inhibition enhances T cell infiltration and activation while suppressing the immunosuppressive functions of tumor-associated macrophages. The dual role of BET proteins in controlling both stemness and immune regulation positions them as central regulators of tumor-intrinsic and immune-mediated mechanisms in cancer. This makes BET proteins attractive therapeutic targets, as their inhibition offers the potential to simultaneously suppress tumor growth and reprogram the immune microenvironment. Preclinical and early clinical studies demonstrate that combining BET inhibitors with chemotherapy, targeted therapies, or immune checkpoint blockade synergizes anti-tumor responses. Future research focused on understanding the context-specific functions of BET proteins, and optimizing combination strategies will be critical to fully harness their therapeutic potential in solid tumors.
Introduction
Bromodomain and extraterminal domain (BET) family of proteins comprising BRD2, BRD3, BRD4, and BRDT function as epigenetic readers that recognize acetylated histones, promoting chromatin accessibility (1). By binding to acetylation marks, BET proteins recruit co-activators and transcriptional machinery to promoter and enhancer regions, facilitating assembly of the pre-initiation complex (2, 3). Additionally, BET proteins support transcriptional elongation by stabilizing RNA polymerase II and interacting with elongation factors (1–4). The molecular biology of BET proteins has been comprehensively reviewed (3).
Although BET proteins share conserved bromodomains, individual BET proteins exhibit non-redundant roles (5). BRD4, the most extensively studied BET protein, recruits P-TEFb to promoters and super-enhancers to drive transcriptional elongation of oncogenes and also contributes to immune evasion (2, 6, 7). BRD2 acts as a scaffold for E2F transcription factors and chromatin-modifying enzymes and can promote therapy resistance through activation of the Ras/ERK pathway (8–10). BRD3 exhibits context-dependent activity: in some tumors it promotes metastasis and tumor progression, whereas in others it has tumor-suppressive effects, positively correlating with p21 expression (11–16). While all BET proteins are broadly expressed in normal tissues, BRDT is predominantly expressed in the testis and ovary (1) with its activity largely confined to spermatogenesis, where it coordinates the chromatin remodeling essential for sperm maturation (17). Functional specificity in BET proteins is largely dictated by the C-terminal, extra-terminal, and coiled-coil domains rather than the bromodomains themselves (18).
In cancer, BET proteins are often overexpressed and contribute to oncogenesis by promoting the transcription of proto-oncogenes (19, 20). Recent findings underscore their role in regulating cancer stem cells (CSCs), a subpopulation of tumor cells with self-renewal potential, therapeutic resistance, and metastatic capacity (21–23). Beyond their tumor-intrinsic effects, BET proteins also modulate the tumor microenvironment (TME) by regulating immune cell function and phenotype.
Two major therapeutic approaches have been developed to target BET proteins: inhibitors, which block bromodomain–acetyl-lysine interactions, and degraders, which use proteolysis-targeting chimeras (PROTACs) to induce selective protein degradation (24, 25). Both BET inhibitors (BETi) and BET degraders (BETd) reduce CSC viability, suppress self-renewal, and enhance chemosensitivity in preclinical models of breast cancer, squamous cell carcinoma, and other tumor types (21, 22, 26–28). While pan-BET inhibitors inhibit BRD2, BRD3, and BRD4, efforts are increasingly focused on inhibitors with paralog- or isoform-specificity. Selective inhibition has differential effects: BRD4 inhibition alone suppresses tumor growth in multiple myeloma, AML, and solid tumors, whereas dual BRD2/BRD4 inhibition is often required in resistant models (6, 29). Emerging BET degraders and PROTACs allow selective targeting of BRD2, BRD3, and BRD4, enabling dissection of these non-redundant roles (30, 31). The development of BRD4-selective inhibitors and ET-domain-targeting molecules offers a promising strategy to enhance therapeutic potency while reducing off-target effects (18, 31–38). Together, these strategies enhance the precision of BET targeting; yet a recent multi-tumor analysis demonstrated that adaptive BRD2 overexpression can sustain transcriptional programs and drive resistance, emphasizing the need to integrate combination or sequential therapies into future treatment approaches (39).
Preclinical studies demonstrate that BET-targeted therapies can reprogram tumor-associated macrophages (TAMs), enhance antigen presentation by dendritic cells, boost cytotoxic activity of T and NK cells, and promote anti-tumor immunity by reducing immunosuppressive cytokines (40, 41). However, these therapies can also negatively affect certain immune subsets, underscoring the need to balance efficacy with immune safety (42, 43). BET inhibitors have advanced to clinical development as promising therapies, with potential synergy with chemotherapy and immunotherapy (44).
This review focuses on BET protein regulation of immune cells in the tumor immune microenvironment, a dynamic ecosystem that engages in bidirectional crosstalk with tumor cells and can exert both pro and anti-tumorigenic effects. BET proteins influence immune evasion, inflammatory signaling, and responsiveness to immunotherapy by modulating immune cell function. Understanding how BET-targeted therapies reprogram the immune cells and identifying the conditions under which they potentiate or suppress immune function, are pivotal for optimizing BET-targeted therapies into clinical practice.
BET proteins in cancer and immune regulation: context and lineage dependency
BET proteins are central transcriptional regulators whose specific roles vary depending on cancer lineage, tumor subtype, and cellular context. This heterogeneity among different cancer types is a result of distinct transcription factor activity, and chromatin and enhancer landscapes across different cancers. BET proteins cooperate with oncogenic drivers that are cancer type specific, including androgen receptor signaling in prostate cancer (45), GLI1 in glioblastoma (46), and MYC activity in hematologic malignancies (47). Even within tumor types, the function of BET proteins can vary; within breast cancer, for example, subtype-specific functions have been described. In estrogen receptor positive tumors, BRD4 cooperates with the estrogen receptor and super-enhancer structures to sustain estrogen-responsive transcriptional programs (48), whereas in triple negative breast cancer (TNBC), BET proteins primarily regulate inflammatory signaling, stemness, EMT, and immune-modulatory axes (22). Recent findings underscore their role in regulating CSCs, a subpopulation of tumor cells with self-renewal potential, therapeutic resistance, and metastatic capacity (9, 22). A comprehensive analysis of bromodomain-containing proteins across cancer types reinforces this heterogeneity, showing that distinct BET genes are differentially expressed in specific tumor lineages (49).This lineage- and cell state-dependence requires a mechanistic and context-specific understanding of BET protein function for successful BET-targeted therapies in the clinic (6).
Beyond tumor-intrinsic effects, BET proteins regulate multiple immune lineages. BRD2 enhances NK-cell cytokine production and cytotoxicity, whereas BRD4 drives inhibitory gene expression via the SMAD4–BRD4 axis (50, 51). In macrophages, BRD4 promotes M2-like polarization through MAF and NRF2/HO-1 signaling, while BRD2 supports pro-inflammatory transcriptional programs (52–54). Neutrophil differentiation is influenced by Znf687-mediated recruitment of a BRD4–SMRT complex to gfi1aa, a transcription factor essential for granulocytic specification (55).
Within the adaptive immune system, BET proteins orchestrate effector differentiation and cytokine output. BRD2 primes Th17 differentiation by increasing early chromatin accessibility, whereas BRD4 sustains high-output IL-17 production (56). BRD4 also promotes terminal differentiation of cytotoxic CD8+ T cells through Id2 and Cx3cr1 super-enhancers (57). In B cells, BRD4 cooperates with NF-κB to induce IL-10 and drive regulatory phenotypes, while BRD2 supports mitogenic expansion and activation (53, 58).
Together, these tumor- and immune-intrinsic functions position BET proteins as central transcriptional integrators that shape malignant behavior, immune activation, and immunosuppressive programs in a highly context-dependent manner.
BET proteins as regulators of the tumor immune microenvironment
The tumor microenvironment consists of malignant cells, immune cells, fibroblasts, and endothelial cells, all organized within a complex extracellular matrix. These cells mediate reciprocal, context-dependent interactions that drive tumor progression, modulate immune evasion, and shape therapeutic outcome (59). While immunotherapies have significantly improved outcomes in hematologic malignancies, their efficacy in solid tumors remains limited (60, 61). Tumor cells, especially CSCs, promote immune evasion and therapy resistance by fostering immunosuppressive niches (62, 63). Given that BET proteins are emerging as critical regulators of TME, they represent a crucial opportunity to improve the function of immunotherapy in solid tumors (41, 54, 64–67).
As shown in Figure 1, immune cells such as cytotoxic T cells, macrophages, dendritic cells, and natural killer (NK) cells use mechanisms including phagocytosis and cytotoxic killing to inhibit tumor growth. However, tumor cells, reshape the immune landscape through oncogenic signaling and the release of immunosuppressive cytokines and chemokines, as well as via cell–cell signaling axes. For instance, tumor-derived cytokines promote macrophage polarization toward a pro-tumor M2 phenotype and suppress phagocytosis through CD47–SIRPα signaling. Additionally, tumor cells evade T cell-mediated cytotoxicity by modulating MHC class I expression and upregulating immune checkpoint ligands such as PD-L1 (68–71).
Figure 1. Reciprocal interactions and immunosuppressive signaling among tumor cells and immune cell populations in the tumor microenvironment. This figure comprehensively illustrates the dynamic interplay between tumor cells and key immune cells including Natural Killer (NK) cells, Macrophages, Dendritic cells, and Cytotoxic T cells within the tumor microenvironment, highlighting both effective anti-tumor immune responses and key mechanisms of immune evasion by cancer cells. NK cells, part of the innate immune system, detect and kill tumor cells when their activating receptors bind ligands on the tumor surface, triggering perforin and granzyme release (light green dots) and inducing tumor cell death. Tumor cells can express MHC-I, which binds to inhibitory receptors on NK cells and deactivates them, contributing to immune evasion. Macrophages play dual roles: they can mediate tumor cell killing via phagocytosis and antibody-dependent mechanisms (Tumor antigen (T.Ag) and FcγR interactions) and activate T cells through reciprocal signaling (gold dots). Tumor cells, however, can express CD47, engaging SIRPα on macrophages to deliver a “don’t eat me” signal, preventing phagocytosis and promoting tumor growth. Tumor-derived immunosuppressive cytokines (red dots) can also polarize macrophages from an anti-tumor M1 phenotype to a pro-tumor M2 phenotype, further supporting tumor progression. The adaptive immune response is initiated by DCs, which capture and present tumor antigens via MHC-I to T-cell receptors (TCRs) on Cytotoxic T cells, leading to activation. Activated Cytotoxic T cells specifically kill tumor cells through perforin and granzyme release (light blue dots). DCs also activate NK cells, enhancing the innate response. Tumor cells evade adaptive immunity by expressing PD-L1, which binds PD-1 on Cytotoxic T cells, inhibiting their activity and promoting tumor escape. Overall, this figure shows the complex balance between immune-mediated tumor destruction and cancer immune evasion, providing insights critical for understanding tumor progression and informing immunotherapeutic strategies. Figure is created with BioRender.
Preclinical studies suggest that BET inhibitors and BET degraders can reshape the tumor immune microenvironment by suppressing pro-tumor inflammation and restoring cytotoxic T and NK cell activity (40, 41, 72). However, responses are heterogeneous across tumor types, reflecting the complex and context-dependent roles of BET proteins. These context-dependent effects may reflect differences in pre-existing immune composition and myeloid versus lymphoid dominance across tumor types. To better understand these effects, it is essential to examine how BET proteins modulate specific immune populations, including innate and adaptive cells, which collectively determine anti-tumor immunity.
BET proteins and natural killer cells
Natural killer (NK) cells are key effectors of innate immunity, capable of directly killing tumor cells via perforin- and granzyme-mediated lysis, apoptosis induction, and secretion of cytokines such as CCL3-5, IFN-γ, and TNF-α (73–75). Their cytotoxicity is regulated by a balance of activating and inhibitory receptors, tuned by the local cytokine milieu (76–79). This balance ensures NK cells selective targeting of MHC-I–deficient/low tumor cells while sparing normal cells (80, 81). During tumor progression, NK cell function is often impaired due to upregulation of inhibitory ligands, and immunosuppressive cytokines, and downregulation of activating receptors such as NKp30 and NKp44 (79, 82–85). These changes impair NK cell recognition and contribute to immune evasion, limiting the efficacy of immunotherapeutic strategies that rely on NK cell activation.
BET proteins influence NK-cell–mediated anti-tumor immunity in a context- and protein-specific manner, affecting both tumor cells and NK-intrinsic functions. For instance, in multiple myeloma, pan-BET inhibition with JQ1(targeting BRD2/BRD3/BRD4/BRDT) increases expression of the NKG2D ligand MICA on tumor cells, enhancing susceptibility to NK-mediated cytotoxicity through a BRD4-dependent mechanism that downregulates c-MYC and alters miR-125b and IRF4 levels (86). In non-small cell lung cancer (NSCLC), BET inhibition with JQ1 and OTX015 disrupts the BRD4-SMAD3 transcriptional axis that drives inhibitory receptor expression on NK cells enhancing NK-cell cytotoxicity and immune-checkpoint molecules (51), whereas in neuroblastoma, JQ1 reduces tumor susceptibility by downregulating ligands for NKG2D and DNAM-1, though the precise mechanisms remain less defined (87). Further, BET inhibitors can synergize with other epigenetic modulators to enhance anti-tumor immunity. In preclinical small-cell lung cancer models, combined BETi (JQ1) and HDAC6 (ACY-1215) produced stronger anti-tumor effects than either agent alone in an NK-dependent manner (40). Figure 2 illustrates both NK cell–intrinsic and tumor cell–intrinsic BET-regulated pathways identified in studies 52 and 87, and shows how BET inhibitors restores NK cell function, disrupts immune evasion, and supports tumor clearance.
Figure 2. BET inhibition enhances NK-cell–mediated anti-tumor immunity through coordinated effects on NK cells and tumor cells. BET inhibitors (BETi) suppress BET protein activity, reshaping both NK-intrinsic signaling and tumor-cell ligand expression. In NK cells, BET targeting downregulates inhibitory receptors (KIR3DL3, KIR2DL1, KLRG1, KIR3DX1) as reported by Regianni et al. (51), while upregulating activating receptors NKG2D and DNAM-1 (Abruzzese et al., 2016), collectively promoting enhanced degranulation and release of perforin (PFN) and granzyme B (GzmB). In tumor cells, BET inhibition reduces MHC-I and MYC expression (51) and decreases MYC while upregulating the NKG2D ligand MICA (Abruzzese et al., 2016), increasing susceptibility to NK-mediated lysis. Together, these NK-intrinsic and tumor-intrinsic effects strengthen enhance cytotoxicity and reduce tumor growth. Solid and dotted lines represent canonical mechanisms and effects of BET inhibition, respectively. Figure is created with BioRender.
Direct effects of BET proteins on NK cells are also demonstrated: BRD4 is essential for cytotoxicity and IFN−γ production, whereas BRD2 primarily modulates cytokine production without impairing cytotoxicity, and the role of BRD3 remains understudied. This is demonstrated by BET protein–specific responses to inhibition: JQ1, which more strongly targets BRD4, suppresses NK-cell cytotoxicity, whereas AZD5153, with greater selectivity for BRD2, maintains cytotoxic function while modulating cytokine output highlighting distinct roles among BET family members (50).
These findings underscore the context-dependent and multifaceted role of BET proteins in NK cell biology. Depending on the BET family member targeted, the mode of inhibition, and whether effects are direct or mediated via the TME, BETi can either suppress or enhance NK cell responses. Dissecting these differential outcomes shaped by tumor type, immune status, BET protein specificity, and treatment dynamics is essential for the rational design of BET-targeted therapies that harness, rather than hinder, NK cell–mediated anti-tumor immunity. Preclinical studies (Table 1) (40, 51, 86) show that BETi, especially in combination with other therapies, can boost NK cell cytotoxicity across tumor models. To optimize efficacy and avoid immune suppression, future strategies should integrate real-time immune profiling, including NK cell subset specific effect and cytokine analysis.
Table 1. Preclinical studies examining the impact of BET inhibitors on NK cells and tumor-associated macrophages (TAMs) mediated tumor immunity.
BET proteins and tumor-associated macrophages
Tumor-associated macrophages (TAMs) are a heterogeneous population of immune cells. They can polarize into two main phenotypes: M1-like macrophages, which exert anti-tumor effects, and M2-like macrophages, which are pro-tumorigenic. M2-like macrophages promote cancer progression by secreting growth factors, and cytokines that drive epithelial-to-mesenchymal transition (EMT), invasion, metastasis, and therapy resistance (88–94). Given their pro-tumorigenic role, strategies to reprogram M2-like macrophages have attracted significant attention (95).
BET protein inhibition has emerged as a promising approach to modulate TAM function. BET inhibitors such as JQ1 and I-BET762 suppress M2-like programming, shifting TAMs toward an anti-tumor M1-like phenotype by downregulating immunosuppressive genes and reducing recruitment of M2-like macrophages (5, 54, 94, 96). These phenotypic shifts are associated with reduced tumor growth and improved responses to immunotherapy (Figure 3). Key preclinical findings supporting these effects are summarized in Table 1 (54, 91, 94, 97, 98).
Figure 3. BET inhibition modulates macrophage polarization in the tumor microenvironment. BET inhibitors (BETi) disrupt BET protein function in tumor cells, leading to reduced secretion of pro-tumorigenic cytokines such as IL-6, CCL2, GM-CSF, and CSF1 that drive M2-like macrophage recruitment, proliferation, and expression of immunosuppressive genes. Diminished CSF1–CSF1R signaling limits self-renewal and colony formation of M2-like (CD68+Mki67+) TAMs, while lowered levels of IL-6, CCL2, and GM-CSF inhibit M2 polarization, as demonstrated by decreased expression of CD163, CCR2, CD206, IL-10, and VEGF. Concurrently, BET inhibition promotes the abundance and MHCII expression of anti-tumor M1-like (CD68+CD80+) macrophages. These coordinated effects not only attenuate TAM-mediated promotion of tumor growth, invasion, and immune suppression, but also facilitate enhanced responses to immunotherapy. Solid and dotted lines represent canonical mechanisms and effects of BET inhibition, respectively. Figure is created with BioRender.
Importantly, individual BET family members have distinct and non-redundant roles in TAMs. BRD4 promotes pro-tumor M2-like polarization by driving MAF transcription, whereas BRD2 contributes predominantly to pro-inflammatory gene expression (52, 53, 99). In pancreatic cancer models, BET inhibition reduces HO-1 expression in macrophages and suppresses tumor-promoting cytokines such as IL-6, CCL2, and GM-CSF, demonstrating a direct link between BET activity and the immunosuppressive tumor microenvironment (99). Beyond polarization, BET inhibitors also impact macrophage self-renewal and survival. JQ1 has been shown to impair GM-CSF-driven peritoneal macrophage self-renewal and IL-4-induced alternative (M2-like) polarization (100), highlighting their ability to simultaneously modulate macrophage proliferation and pro-tumor function. In ovarian cancer, targeting CCR2+ TAMs with BRD4 specific inhibitor (ABBV-075) selectively depletes this pro-tumor subset, overcoming adaptive resistance to anti-VEGF therapy while sparing M1-like macrophages (94).
Despite promising findings, resistance to BET-targeted therapies have been observed, particularly in TNBC, where TAMs sustain tumor growth through IL-6/IL-10–driven STAT3/NF-κB signaling (96). This highlights the need to overcome compensatory mechanisms that allow TAMs to maintain pro-tumor functions despite BET inhibition. Combination therapies may hold the key to addressing this issue. Co-targeting BET proteins along with key pro-tumor pathways, such as IKBKE or STAT3 signaling, has shown potential to disrupt macrophage polarization and inflammatory signaling simultaneously (64, 101). In addition, direct targeting of cytokines such as IL-6, which is already being targeted clinically with agents like tocilizumab, could potentially be explored in combination with BET inhibitor to further suppress tumor-promoting inflammation (102, 103).
Together, these findings emphasize that BET proteins orchestrate TAM phenotype, proliferation, and survival in a context- and protein-specific manner, and that selective targeting of BET proteins, particularly BRD4, along with rational combination strategies, may optimize TAM reprogramming and overcome resistance, highlighting the therapeutic potential of BET inhibitors in modulating the tumor microenvironment.
BET proteins and neutrophils
Neutrophils are the most abundant innate immune cells and play central roles in host defense and inflammatory responses (104). Within the TME, neutrophils constitute a major infiltrating population (105) and exhibit phenotypic and functional heterogeneity (106–108). Tumor-associated neutrophils (TANs) can adopt anti-tumor (N1) or pro-tumor (N2) states, thereby contributing either to tumor suppression or promotion (104, 109). High TAN levels are generally associated with poor prognosis and reduced therapeutic responses across many cancer types (106–108).
Recent studies have expanded our understanding of BET proteins in neutrophil biology beyond their classical transcriptional roles. In zebrafish hematopoiesis, Znf687 recruits a BRD4–SMRT complex to regulate gfi1aa, a transcription factor essential for neutrophil lineage specification (55). Although studied in development, this mechanism highlights BRD4 role in neutrophil differentiation raising the possibility that BET proteins could shape TAN composition and maturation in tumors. In a Th17-driven murine model of severe refractory asthma, the pan-BET inhibitor CPI-203 reshaped inflammatory cytokine networks, increasing IL-1α, IL-1β, IL-2, IL-6, IL-10, IL-12 isoforms, IL-13, and IL-17A, while decreasing G-CSF, CXCL1, MIP-1β, and CCL5 (110, 111). These results demonstrate that BET inhibition alters cytokine circuits controlling neutrophil trafficking (110). Similarly, in a renal ischemia–reperfusion injury model, BRD4 inhibition dampened neutrophil activation, indicating that BET proteins influence neutrophil effector response in tissue stress (112).
Together, these studies highlight BET proteins as regulators of differentiation of cytokine networks and neutrophil effector functions. Although no studies have directly examined BET proteins in neutrophils in cancer, evidence from developmental and inflammatory models suggests they may influence TAN maturation and functional plasticity (110). Given the critical role of TANs in tumor progression, metastasis, and therapy resistance (113), investigating BET-mediated regulation of neutrophils in the TME represents an important and unexplored area in cancer epigenetics.
BET proteins and dendritic cells
Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that form a critical link between innate and adaptive immunity. In the TME, DCs sense damage-associated molecular patterns (DAMPs) such as calreticulin, ATP, and HMGB1 released during immunogenic cell death (ICD) (114). This sensing promotes the uptake of tumor antigens and DC maturation. Mature DCs then present tumor antigens via MHC molecules to T cells, driving cytotoxic immune responses critical for effective immunotherapy (115, 116). However, the immunosuppressive TME impairs DC function by skewing them toward tolerogenic phenotypes through tumor-derived cytokines, downregulation of co-stimulatory molecules, and upregulation of immune checkpoint (IC) ligands, ultimately dampening T-cell activation and anti-tumor immunity (117, 118).
BET protein targeting exerts context-dependent effects on DCs, with both direct and indirect mechanisms. In a colorectal cancer model, PROTAC-mediated degradation of BET proteins (BRD2, BRD3, and BRD4) in tumor cells induces immunogenic cell death and activates DR5-mediated apoptosis. This leads to enhanced release of DAMPs that promote DC-mediated phagocytosis and cross-presentation, indirectly boosting DC function (65). In contrast, direct exposure of DCs to pan-BET inhibitors, such as JQ1 or I-BET151, suppresses DC maturation. Under these conditions, LPS-induced upregulation of co-stimulatory molecules (CD80, CD86, CD40) and MHC class II is reduced, resulting in impaired T-cell priming (42, 43, 119). Mechanistically, JQ1 inhibits STAT5 phosphorylation and nuclear translocation in human DCs, which is essential for the expression of maturation markers (119)While previous studies suggests that BRD2 may be the predominant BET family member regulating STAT5 (120) isoform-specific knockdowns have not yet been performed in DCs (120–122) so the contributions of BRD3, BRD4, and BRDT remain unresolved.
These findings highlight the context-dependent effects of BET targeting on DC biology. Future strategies should focus on optimizing dosing regimens and exploring combination therapies that preserve DC maturation while enhancing their activation, ultimately improving BET-based immunotherapeutic outcomes.
BET proteins and T cells
T lymphocytes (T cells) are a key component of adaptive immunity, responsible for identifying and eliminating malignant cells (123). In the TME, CD8+ cytotoxic T cells recognize tumor antigens presented on MHC-I molecules and induce tumor cell death via perforin and granzyme release (124). CD4+ helper T cells enhance this response by supporting the activation of cytotoxic T cells, NK cells, and B cells. Conversely, regulatory T cells (Tregs) contribute to immune suppression within tumors, limiting effective anti-tumor responses (123, 125). T cell dysfunction in tumors is driven by the upregulation of immune checkpoints (ICs) and the secretion of suppressive cytokines, both of which contribute to immune suppression in the TME (126–129). Tumor cells overexpress ligands like PD-L1, engaging PD-1 receptors on T cells and leading to exhaustion and loss of cytotoxicity (130–134). Chemotherapy can worsen this by enriching IC-positive cancer cells (135). Additionally, tumors suppress T cell responses by downregulating MHC-I, secreting immunosuppressive cytokines, and expanding Tregs (64, 136–139). While IC inhibitors (ICIs) have improved outcomes for a subset of patients, many tumors remain resistant due to poor immune cell infiltration and the suppressive anti-tumor (132, 133).
BET inhibitors have recently been recognized as modulators of T cell infiltration and anti-tumor immune responses. For example, BET inhibitor I-BET51 enhanced CD8+ T cell infiltration and reduced tumor growth in ovarian cancer (72). JQ1 decreased PD-L1 expression through BRD4-dependent occupancy of the CD274 promoter, thereby increasing tumor-associated CD8+ T cells producing IFN-γ and granzyme B in lymphoma, prostate, and oral squamous cell carcinoma models (140–142). This underscores a BRD4-specific role in anti-tumor immunity, further supported by adoptive transfer studies, where BRD4 inhibition via the BRD4–p300 axis enhanced BATF expression, improving persistence and anti-tumor activity in adoptive T cell and CAR-T models (143). Similarly, BRD4-specific inhibition (SZU-119) augmented CD8+ T cell infiltration, cytotoxicity, and PD-L1 suppression to a greater degree compared with pan-BET inhibitors (144). These studies indicate that BET inhibitor selectivity influences T cell infiltration and cytotoxicity. In addition to selectivity, the therapeutic context such as cancer type or combination therapy further determines anti-tumor efficacy. For example, in hepatocellular carcinoma, JQ1 alone increased PD-L1 via Rab8A, but combining JQ1 with anti-PD-L1 restored cytotoxicity and reduced tumor progression (145). Similarly, enzyme-responsive micellar JQ1 (mJQ1) enhanced tumor suppression and CD8+ T cell activation compared with free JQ1 in B16F10 melanoma, particularly when combined with radiotherapy (146). These studies highlight the potential of BET inhibitors in combination immunotherapies.
BET inhibitors can synergize with complementary strategies to enhance anti-tumor T cell responses. They sustain stem-like CD8+ T cells and improve persistence and cytotoxicity (143). JQ1 combined with checkpoint blockade (anti-PD-1 or anti-CTLA-4) improved CD8+/Treg ratios and Th1 activation in melanoma and lung adenocarcinoma models (147), and similarly enhanced anti-tumor T cell responses in prostate cancer models (141). More recently, BET inhibitors paired with anti-KLRG1 antibodies or IL-2 complexes selectively depleted tumor Tregs and enhanced CD8+ cytotoxicity (148). In addition, BET inhibitors (RG6146 and JQ1) sensitize tumor cells to TNF-mediated cytotoxicity by blocking BRD4-dependent NF-κB survival programs in tumor cells. This enhances tumor cell apoptosis in the presence of TNF and, when combined with T-cell bispecific antibodies or IC blockade, increased bystander tumor killing. Overall, BET inhibitors restores T cell function by downregulating IC molecules on T cells and suppressing PD-L1 on tumors, enhancing cytotoxicity and reducing tumor progression (62, 140, 149) as shown in Figure 4. Key findings from these models are summarized in Table 2 (72, 98, 141, 142, 144–146, 148, 150, 151).
Figure 4. BET inhibition modulates effector and regulatory T cell function in the tumor microenvironment. BET inhibitors (BETi) impact both effector CD8+ T cells and regulatory CD4+ T cells in the tumor microenvironment, reshaping anti-tumor immune responses. BET inhibitors enhance CD8+ T cell activity by increasing IFN-γ+ cells and memory precursor populations, while reducing the exhaustion phenotype. BETi also upregulate MHC-I and cytokine expression in tumor cells, diminishing tumor escape and growth. In regulatory T cells, BET inhibition decreases Foxp3+ Tregs and increases naïve memory T cells, further alleviating tumor-mediated immunosuppression. Additionally, BETi downregulate inhibitory receptors (PD-1, CTLA-4, TIM-3) and the checkpoint ligand PD-L1, promoting robust anti-tumor T cell responses. Solid and dotted lines indicate canonical mechanisms and effects of BET inhibition, respectively. Figure is created with BioRender.
Table 2. BET protein targeted anti-tumor immunity mediated by T and B cells.
Although BET-targeted therapies hold significant therapeutic potential, BET proteins play context-dependent roles in T cell biology, with inhibitors showing protein and subset-specific effects. Early studies using pan-BET inhibitors demonstrated that I-BET762 reduces proliferation and cytokine production in CD4+ T cells, including IL-17, IFN-γ, and GM-CSF, affecting Th1, Th2, and Th17 subsets (152–154). JQ1 selectively inhibits Th17 differentiation by blocking BRD2/BRD4 binding at IL-17 loci, whereas I-BET762 broadly suppresses Th1 and Th2 cytokines (153). Mechanistic studies showed that BRD2 facilitates early chromatin accessibility to initiate Th17 differentiation, while BRD4 acts as a transcriptional amplifier to sustain high IL-17 production; selective BD1 inhibition with MS402 disrupts Th17 maturation without affecting other subsets (56, 155). Furthermore, BRD4 also drives terminal effector (TE) CD8+ T cell differentiation by promoting transcription of Id2 and Cx3cr1 at super-enhancers, whereas loss of BRD4 shifts cells toward memory precursor phenotypes (57). These findings emphasize that BET inhibitor selectivity, dosage, and cellular context critically determine T cell outcomes (153, 154).
To address the complex and context-dependent effects of BET inhibitors on T cell biology, we propose several alternative strategies. For instance, designing selective BET inhibitors that preferentially target BRD4 while sparing BRD2 and BRD3 could help preserve T helper cell function as shown in previous studies (143, 144). In preclinical models, the BET bromodomain inhibitor EP11313 was shown to suppressed pathogenic effector T-cell responses while preserving regulatory T-cell (Treg) function, maintaining IL-10 and TGF-β production (156). These findings highlight the potential to develop BET inhibitors that selectively deplete tumor-associated Tregs while enhancing cytotoxic CD8+ T-cell responses. By reshaping the tumor immune microenvironment in this way, such inhibitors could boost anti-tumor immunity and synergize with checkpoint blockade or T-cell–redirecting therapies to improve therapeutic efficacy. Furthermore, optimizing intermittent dosing schedules may allow transient BET inhibition while enabling recovery of normal T cell proliferation and differentiation. Combining BET inhibitors with agents that support T cell activation and survival, such as cytokine therapies (e.g. IL-2, IL-7, IL-21) or co-stimulatory receptor agonists (e.g. OX40, 4-1BB) could enhance cytotoxic responses without increasing T cell dysfunction. Triplet strategies that integrate BET inhibitors with immune checkpoint blockade and either co-stimulatory agonists or Treg-depleting therapies may amplify anti-tumor immunity while maintaining immune balance. Together, these approaches emphasize the need for context-aware and carefully modulated BET targeted application in T cell–based cancer immunotherapy.
BET proteins and B cells
B cells, a key lymphocyte subtype for humoral immunity, produce antibodies in response to antigen recognition. In cancer immunity, B cells exhibit dual roles based on their phenotype in TME. Effector B cells exert anti-tumor activity through complement activation and antibody production, while regulatory B cells (Bregs) can suppress immune responses by secreting suppressive cytokines and expressing immune checkpoint molecules in response to tumor-derived cytokines (157). Bregs, known for their IL-10 production, have been identified in various cancers (58), and can promote tumor growth by releasing anti-inflammatory mediators and increasing expression of inhibitory molecules such as PD-L1 (158, 159).
Mechanistically, BET proteins are implicated in these regulatory functions. BRD4 associates with NF-κB at the IL-10 promoter in Bregs, and pharmacological inhibition with JQ1 disrupts this interaction, reducing IL-10 production and secretion (58, 158). This suggests that BET inhibitors could potentially counteract the tumor-promoting effects of Bregs. In a similar study, JQ1 treatment reduces B cell class switching, immunoglobulin expression, and antibody secretion (160). The IL-10 suppression appears primarily mediated via BRD4, whereas the reduction in class switching, immunoglobulin expression, and antibody secretion in effector B cells reflects broader BET inhibition. These differing outcomes demonstrate that while BET inhibition can suppress tumor-promoting Breg activity, it may simultaneously impair beneficial effector B cell functions. BRD2, on the other hand, has been linked to general B cell expansion and mitogenesis (161).
While targeting Bregs with BET inhibitors holds therapeutic potential, balancing the effects on effector and regulatory B cell populations will be crucial. The challenge lies in selectively modulating the immunosuppressive functions of Bregs without disrupting the essential antibody-mediated immune responses provided by effector B cells.
Translational potential of BET targeting in cancer therapy
Preclinical studies establish BET proteins as pivotal regulators of both tumor cells and immune cells within the tumor microenvironment. BET inhibitors effectively modulate transcriptional programs critical for cancer cell survival, proliferation, and immune evasion (3, 24). Collectively, these findings provide a strong rationale for further exploration of BET-targeted therapies across multiple malignancies (19, 162–165). Previous reviews have comprehensively summarized BET inhibitor and PROTAC combination strategies highlighting synergy with chemotherapeutics, targeted therapies, and immunotherapies, and supporting continued preclinical and clinical studies.
Recent preclinical studies demonstrate that BET inhibitors exhibit robust anti-tumor activity as monotherapy across diverse cancers. They induce DNA damage, cell-cycle arrest, and apoptosis while suppressing oncogenic signaling pathways such as IL-6 and BRD4/STRADA/CCND1 (166–169). BRD4-specific inhibitors restore sensitivity to osimertinib in resistant EGFR-mutant lung cancer (170), and induce autophagy-dependent differentiation in glioblastoma (169). Innovative strategies, such as JQ1-loaded nanoplatforms with improved tumor targeting (171) and OPT-0139, a dual BRD4/nitric oxide donors, further enhance therapeutic efficacy (172). Notably, a case report described an exceptional response to BMS-986158 (BETi) in a patient with BRD4-NUTM1 NUT carcinoma harboring a BRD4 splice-site mutation, highlighting the potential for personalized BET-targeted therapy (173). Targeting BRD3 also effectively suppresses nuclear TYRO3-driven metastasis in colorectal cancer, underscoring BRD3 as a promising therapeutic target to prevent tumor dissemination (14).
Preclinical studies demonstrate that BET inhibitors enhance the efficacy of radiation therapy across multiple cancer models. In breast cancer, BRD4 inhibitor combined with radiotherapy reduced PD-L1 and HIF-1α expression, remodeled myeloid cells toward an immunostimulatory phenotype, and expanded CD4+/CD8+ T cell populations (174). Similarly, BET blockade increases radiosensitivity in glioma and lung cancer by promoting DNA damage and G2/M checkpoint arrest (175), while in glioblastoma it suppresses super-enhancer-driven COL1A1, impairing DNA repair and enhancing tumor cell death (176). BET inhibitors also synergize with targeted radiotherapy, as shown by combination with the PSMA-directed alpha-emitting radioligand [²¹²Pb]Pb-AB001, which further suppresses prostate cancer growth in vitro (177). Together, these studies highlight BET inhibition as a versatile radiosensitization strategy acting through both tumor-intrinsic and immune-mediated mechanisms.
BET inhibitors also synergize with targeted therapies to enhance anti-tumor efficacy across diverse cancers. CBX3-targeted dual BET/PLK1 inhibition amplifies the effects of CDK4/6 inhibitors by disrupting BRD4/PLK1-mediated transcription and inducing cell-cycle arrest in prostate cancer (178). In melanoma, BET blockade increases sensitivity to the multi-kinase inhibitor sunitinib by suppressing GDF15, promoting apoptosis, and reducing proliferation (179). Co-inhibition of BET and CDK4/6 further destabilizes BRD4 and impairs homologous recombination in breast cancer (180). Similarly, dual PARP1-BRD4 inhibition enhances DNA damage response and anti-tumor activity in breast cancer, while sequential PARP and BET blockade synergistically suppresses glioblastoma growth (181, 182). Targeting BRD4-mediated YAP1 expression in MEK-resistant melanomas also potentiates trametinib therapy, producing strong anti-tumor synergy (183). Beyond single-target combinations, dual HDAC3/BRD4 inhibitors simultaneously disrupt oncogenic transcription and chromatin regulation, broadly enhancing apoptosis across multiple tumor models (184). Collectively, these studies demonstrate that BET inhibitors can be rationally paired with diverse targeted agents to overcome resistance mechanisms and amplify therapeutic responses.
In addition to targeted therapies, BET inhibitor demonstrate potent synergy with immunotherapeutic strategies, reshaping the tumor immune microenvironment and enhancing anti-tumor immunity (Tables 1 and 2). In murine models of small-cell lung cancer, melanoma, and TNBC, BET inhibitor enhances tumor antigen presentation, increases cytotoxic T cell infiltration, and synergizes with PD-1/PD-L1 or CTLA-4 checkpoint blockade (185). In TNBC, combining BET inhibitor with paclitaxel and PD-L1 blockade further remodels the tumor microenvironment, promoting immunogenic and senescent transcriptional programs that enhance therapeutic efficacy (186). Complementing these effects, epigenetic modulation with BET inhibitors paired with a TLR7/8 agonist increases T-cell infiltration and activates innate immune signaling, further suppressing tumor growth (187). Novel combinations such as BET inhibitors with SMAC mimetics (SMACm) in PDAC models synergistically inhibit tumor growth, induce multiple cell death pathways, and remodel the immunosuppressive tumor microenvironment to enhance anti-tumor immunity (188). Innovative strategies also include combining BET inhibitor with the BCG vaccine in melanoma, which reprograms T cells toward an activated state, enhances cytotoxicity, reduces exhaustion, increases intratumoral recruitment, and converts “cold” tumors into “hot” tumors, with efficacy confirmed in humanized PDX models (189).
Triple-combination strategies build on these synergistic effects, simultaneously targeting multiple oncogenic or epigenetic pathways to maximize anti-tumor activity. In malignant peripheral nerve sheath tumors, co-inhibition of MEK, BET, and CDK suppresses tumor growth, outperforming single or dual treatments (190). In bladder cancer, the combination of a BET inhibitor with entinostat and cisplatin enhances DNA damage and apoptotic signaling, producing superior anti-tumor efficacy relative to individual or dual agents (191). These preclinical findings illustrate that rationally designed triple combinations can integrate epigenetic, chemotherapeutic, and signaling-targeted interventions to overcome resistance mechanisms and elicit robust therapeutic responses.
Extensive preclinical data demonstrate the efficacy of BET inhibitors both as monotherapy and in combination with radiation, targeted therapies, and immunotherapies. Early-phase clinical trials have begun translating these findings into patient care. Multiple studies (Table 3) are currently evaluating BET modulation in solid tumors, with primary endpoints including efficacy, safety, and immune biomarkers. In hematologic malignancies, a phase I trial of PLX51107 combined with azacitidine in relapsed or refractory myeloid cancers was generally well-tolerated and showed preliminary clinical activity, supporting further investigation of BET inhibitors with hypomethylating agents (192). Similarly, TQB3617 produced a 31% response rate in relapsed/refractory lymphoma, while RO6870810, either as monotherapy in diffuse large B-cell lymphoma or combined with daratumumab, demonstrated manageable safety and early efficacy signals, underscoring the broad potential of BET-targeted therapies across malignancies (193).
Table 3. Ongoing clinical trials of BET inhibitors or degraders alone or in combination.
In solid tumors, early clinical evaluation remains limited but promising. AZD5153, a bivalent BRD4 inhibitor, showed dose-dependent pharmacodynamic activity and a partial response in metastatic pancreatic cancer when administered alone or with Olaparib (194). PLX2853, tested in ARID1A-mutated gynecologic cancers and in combination with carboplatin for platinum-resistant ovarian cancer, demonstrated a favorable safety profile, with modest clinical responses, indicating feasibility and supporting exploration of combination strategies with agents targeting compensatory pathways such as PI3K (195). Conversely, a Phase 1b study combining RO6870810 with the PD-L1 inhibitor atezolizumab in ovarian cancer and TNBC revealed increased immune-related toxicity without synergistic benefit, highlighting the need for careful optimization of immunotherapy combinations (196). More recently, BI 894999 was evaluated in advanced solid tumors, diffuse large B-cell lymphoma, and NUT carcinoma, showing target engagement and tolerable safety, though clinical responses were limited, emphasizing the challenges of BET monotherapy and the rationale for continued combination-focused development (197).
Future clinical strategies should focus on optimizing dosing schedules, incorporating biomarker-driven patient selection, and considering sequential rather than concurrent administration to enhance efficacy while minimizing toxicity. Incorporating immunomodulatory agents into combination regimens may mitigate immune toxicity and enhance therapeutic synergy. High-dimensional profiling and advanced preclinical models (e.g., humanized mice, tumor-organoid co-cultures) provide valuable tools to evaluate these strategies and support rational trial design, including identification of immune biomarkers and patient stratification.
Discussions and perspectives
BET proteins play a critical role in regulating tumor progression and immune modulation within the TME. BET inhibition can disrupt oncogenic transcriptional programs while reprogramming immune dynamics promoting inflammatory macrophage polarization, enhancing NK cell activity, and reshaping T and B cell responses. These multifaceted effects make BET inhibitors promising candidates for cancer immunotherapy, particularly in combination with immune checkpoint blockade (150, 185, 198).
However, a recent clinical study combining BETi with checkpoint inhibitors revealed significant limitations, including immune-related toxicity and limited synergy (196), underscoring the context-dependent nature of BET-mediated immune modulation. Adding to this complexity, BET inhibitors and PROTACs have been shown to suppress IFN-γ production in NK and dendritic cells, alter T cell cytokine profiles, and expand regulatory T cell activity that may compromise anti-tumor immunity. These immune outcomes vary widely depending on the specific immune cell type, differentiation state, and tumor context (58, 153, 161).
To address these challenges, we propose rationally designed dual or triplet combinations to counterbalance BETi-induced immune suppression. Since IFN-γ is critical not only for NK cell cytotoxicity but also for macrophage activation, dendritic cell function, and T cell effector responses (199) combining BETi with immunostimulatory agents may restore essential immune pathways. For example, STING agonists can enhance IFN-γ signaling (200), while IL-2/IL-7 cytokine agonists (201, 202) and co-stimulatory receptor agonists such as OX40 or 4-1BB (203, 204) promote T cell activation. Although these combinations have not yet been tested with BET inhibitors, their complementary mechanisms present promising avenues for future investigation. Furthermore, intermittent or context-specific dosing strategies may attenuate immune exhaustion and preserve effector T cell function.
Future research should focus on elucidating the molecular mechanisms underlying the contradictory immune effects of BET inhibitors. Advanced preclinical models such as humanized mice and tumor-organoid co-cultures are essential to better recapitulate human tumor-immune interactions and predict clinical responses. High-dimensional profiling platforms, including single-cell RNA sequencing and spatial transcriptomics, offer unparalleled resolution to identify the cellular mechanisms of response and resistance. These approaches are particularly powerful for identifying rare immune subsets, mapping cell–cell interactions within the TME and characterizing treatment-induced changes. Such insights will be critical for guiding the rational integration of BET-based therapies into next-generation immuno-oncology strategies (205).
Additionally, defining the distinct immunologic roles of individual BET family members such as BRD2 versus BRD4 in specific immune subsets will be crucial for developing more selective, safer BET-targeted therapies. With a deeper mechanistic understanding of BET proteins’ roles in immune function, and the development of strategic combination approaches, BET inhibitors hold strong potential to become effective and immune-compatible cancer therapies.
Author contributions
DS: Writing – original draft, Writing – review & editing, Visualization, Conceptualization. GB: Conceptualization, Writing – review & editing, Visualization. AK: Visualization, Writing – review & editing. CH: Writing – review & editing. MB: Writing – review & editing, Conceptualization, Funding acquisition, Supervision.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This work was supported by grants from: The Rogel Cancer Center Breast Cancer RFA, and the Rogel Cancer Center Support Grant.
Acknowledgments
We thank Cody Hager (University of Michigan) for his help with reviewing the manuscript. The figures were generated by BioRender.com.
Conflict of interest
The authors declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
1. Fujisawa T and Filippakopoulos P. Functions of bromodomain-containing proteins and their roles in homeostasis and cancer. Nat Rev Mol Cell Biol. (2017) 18:246–62. doi: 10.1038/nrm.2016.143
2. Donati B, Lorenzini E, and Ciarrocchi A. Brd4 and cancer: going beyond transcriptional regulation. Mol Cancer. (2018) 17:164. doi: 10.1186/s12943-018-0915-9
3. Wang ZQ, Zhang ZC, Wu YY, Pi YN, Lou SH, Liu TB, et al. Bromodomain and extraterminal (Bet) proteins: biological functions, diseases, and targeted therapy. Signal Transduct Target Ther. (2023) 8:420. doi: 10.1038/s41392-023-01647-6
4. Sur I and Taipale J. The role of enhancers in cancer. Nat Rev Cancer. (2016) 16:483–93. doi: 10.1038/nrc.2016.62
5. Filippakopoulos P and Knapp S. Targeting bromodomains: epigenetic readers of lysine acetylation. Nat Rev Drug Discov. (2014) 13:337–56. doi: 10.1038/nrd4286
6. Alqahtani A, Choucair K, Ashraf M, Hammouda DM, Alloghbi A, Khan T, et al. Bromodomain and extra-terminal motif inhibitors: A review of preclinical and clinical advances in cancer therapy. Future Sci OA. (2019) 5:FSO372. doi: 10.4155/fsoa-2018-0115
7. Liu Y, Cai L, Wang H, Yao L, Wu Y, Zhang K, et al. Brd4 promotes immune escape of glioma cells by upregulating pd-L1 expression. J Neurooncol. (2025) 171:669–79. doi: 10.1007/s11060-024-04889-8
8. Peng J, Dong W, Chen L, Zou T, Qi Y, and Liu Y. Brd2 is a tbp-associated protein and recruits tbp into E2f-1 transcriptional complex in response to serum stimulation. Mol Cell Biochem. (2007) 294:45–54. doi: 10.1007/s11010-006-9223-6
9. Tian XP, Cai J, Ma SY, Fang Y, Huang HQ, Lin TY, et al. Brd2 induces drug resistance through activation of the rasgrp1/ras/erk signaling pathway in adult T-cell lymphoblastic lymphoma. Cancer Commun (Lond). (2020) 40:245–59. doi: 10.1002/cac2.12039
10. Pecci V, Borsa M, Aiello A, De Martino S, Cis L, Ripoli C, et al. Bromodomain and extra-terminal family proteins brd2, brd3, and brd4 contribute to H19-dependent transcriptional regulation of cell adhesion molecules, modulating metastatic dissemination program in prostate cancer. Noncoding RNA. (2025) 11:33. doi: 10.3390/ncrna11030033
11. Lamonica JM, Deng W, Kadauke S, Campbell AE, Gamsjaeger R, Wang H, et al. Bromodomain protein brd3 associates with acetylated gata1 to promote its chromatin occupancy at erythroid target genes. Proc Natl Acad Sci U.S.A. (2011) 108:E159–68. doi: 10.1073/pnas.1102140108
12. Roberts TC, Etxaniz U, Dall’Agnese A, Wu SY, Chiang CM, Brennan PE, et al. Brd3 and brd4 bet bromodomain proteins differentially regulate skeletal myogenesis. Sci Rep. (2017) 7:6153. doi: 10.1038/s41598-017-06483-7
13. Seifritz T, Brunner M, Camarillo Retamosa E, Maciukiewicz M, Krosel M, Moser L, et al. Brd3 regulates the inflammatory and stress response in rheumatoid arthritis synovial fibroblasts. Biomedicines. (2023) 11:3188. doi: 10.3390/biomedicines11123188
14. Hsu PL, Chien CW, Tang YA, Lin BW, Lin SC, Lin YS, et al. Targeting brd3 eradicates nuclear tyro3-induced colorectal cancer metastasis. Sci Adv. (2023) 9:eade3422. doi: 10.1126/sciadv.ade3422
15. Hashimoto M, Masuda T, Nakano Y, Tobo T, Saito H, Koike K, et al. Tumor suppressive role of the epigenetic master regulator brd3 in colorectal cancer. Cancer Sci. (2024) 115:1866–80. doi: 10.1111/cas.16129
16. Sun W, Cheng J, Zhao R, Xiang Y, Li Y, Yu C, et al. Ku70 targets brd3-myc/cyclin D1 axis to drive hepatocellular carcinoma progression. Exp Cell Res. (2025) 444:114404. doi: 10.1016/j.yexcr.2024.114404
17. Shang E, Nickerson HD, Wen D, Wang X, and Wolgemuth DJ. The first bromodomain of brdt, a testis-specific member of the bet sub-family of double-bromodomain-containing proteins, is essential for male germ cell differentiation. Development. (2007) 134:3507–15. doi: 10.1242/dev.004481
18. Werner MT, Wang H, Hamagami N, Hsu SC, Yano JA, Stonestrom AJ, et al. Correction: comparative structure-function analysis of bromodomain and extraterminal motif (Bet) proteins in a gene-complementation system. J Biol Chem. (2020) 295:6251. doi: 10.1074/jbc.AAC120.013771
19. Sarnik J, Poplawski T, and Tokarz P. Bet proteins as attractive targets for cancer therapeutics. Int J Mol Sci. (2021) 22:11102. doi: 10.3390/ijms222011102
20. Loven J, Hoke HA, Lin CY, Lau A, Orlando DA, Vakoc CR, et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell. (2013) 153:320–34. doi: 10.1016/j.cell.2013.03.036
21. Tian T, Guo T, Zhen W, Zou J, and Li F. Bet degrader inhibits tumor progression and stem-like cell growth via wnt/beta-catenin signaling repression in glioma cells. Cell Death Dis. (2020) 11:900. doi: 10.1038/s41419-020-03117-1
22. Sharma D, Hager CG, Shang L, Tran L, Zhu Y, Ma A, et al. The bet degrader zbc260 suppresses stemness and tumorigenesis and promotes differentiation in triple-negative breast cancer by disrupting inflammatory signaling. Breast Cancer Res. (2023) 25:144. doi: 10.1186/s13058-023-01715-3
23. Czerwinska P and Mackiewicz AA. Bromodomain (Brd) family members as regulators of cancer stemness-a comprehensive review. Int J Mol Sci. (2023) 24:995. doi: 10.3390/ijms24020995
24. Shorstova T, Foulkes WD, and Witcher M. Achieving clinical success with bet inhibitors as anti-cancer agents. Br J Cancer. (2021) 124:1478–90. doi: 10.1038/s41416-021-01321-0
25. Zhou XL, Zhao F, Xu YT, Guan YY, Yu T, Zhang YZ, et al. A comprehensive review of bet-targeting protacs for cancer therapy. Bioorg Med Chem. (2022) 73:117033. doi: 10.1016/j.bmc.2022.117033
26. Xavier PLP, Cordeiro YG, Alexandre PA, Pires PRL, Saranholi BH, Silva ER, et al. An epigenetic screening determines bet proteins as targets to suppress self-renewal and tumorigenicity in canine mammary cancer cells. Sci Rep. (2019) 9:17363. doi: 10.1038/s41598-019-53915-7
27. Singh B, Sarli VN, Milligan RD, Kinne HE, Shamsnia A, Washburn LJ, et al. Sensitization of resistant cells with a bet bromodomain inhibitor in a cell culture model of deep intrinsic resistance in breast cancer. Cancers (Basel). (2023) 15:2036. doi: 10.3390/cancers15072036
28. Dong J, Li J, Li Y, Ma Z, Yu Y, and Wang CY. Transcriptional super-enhancers control cancer stemness and metastasis genes in squamous cell carcinoma. Nat Commun. (2021) 12:3974. doi: 10.1038/s41467-021-24137-1
29. Scicchitano S, Garofalo C, Stella B, Santamaria G, Cozzolino F, Monaco V, et al. Overcoming bet-inhibitor jq1 resistance in aggressive non-small cell lung cancer by inducing ferroptosis via inhibition of the brd2-fth1 axis. FEBS J. (2025) 292:6345–64. doi: 10.1111/febs.70191
30. Muddassir M, Soni K, Sangani CB, Alarifi A, Afzal M, Abduh NAY, et al. Bromodomain and bet family proteins as epigenetic targets in cancer therapy: their degradation, present drugs, and possible protacs. RSC Adv. (2020) 11:612–36. doi: 10.1039/d0ra07971e
31. Kong Y, Lan T, Wang L, Gong C, Lv W, Zhang H, et al. Brd4-specific protac inhibits basal-like breast cancer partially through downregulating klf5 expression. Oncogene. (2024) 43:2914–26. doi: 10.1038/s41388-024-03121-1
32. Hu R, Wang WL, Yang YY, Hu XT, Wang QW, Zuo WQ, et al. Identification of a selective brd4 protac with potent antiproliferative effects in ar-positive prostate cancer based on a dual bet/plk1 inhibitor. Eur J Med Chem. (2022) 227:113922. doi: 10.1016/j.ejmech.2021.113922
33. Hu J, Hu B, Xu F, Wang M, Qin C, McEachern D, et al. Precise conformational control yielding highly potent and exceptionally selective brd4 degraders with strong antitumor activity. J Med Chem. (2023) 66:8222–37. doi: 10.1021/acs.jmedchem.3c00520
34. To KKW, Xing E, Larue RC, and Li PK. Bet bromodomain inhibitors: novel design strategies and therapeutic applications. Molecules. (2023) 28:3043. doi: 10.3390/molecules28073043
35. Huang QX, Fan DM, Zheng ZZ, Ran T, Bai A, Xiao RQ, et al. Peptide inhibitor targeting the extraterminal domain in brd4 potently suppresses breast cancer both in vitro and in vivo. J Med Chem. (2024) 67:6658–72. doi: 10.1021/acs.jmedchem.4c00141
36. Hamilton G, Stickler S, and Rath B. Bromodomain protein-directed agents and myc in small cell lung cancer. Curr Cancer Drug Targets. (2024) 24:930–40. doi: 10.2174/0115680096272757231211113206
37. Wang XB, Meng RJ, Cao WJ, Cheng L, Zhang J, and Chen SW. Targeting brd4 in cancer therapy: from inhibitors and degraders to novel combination strategies and resistance mechanisms. Bioorg Med Chem. (2025) 132:118473. doi: 10.1016/j.bmc.2025.118473
38. Qian H, Zhu M, Tan X, Zhang Y, Liu X, and Yang L. Super-enhancers and the super-enhancer reader brd4: tumorigenic factors and therapeutic targets. Cell Death Discov. (2023) 9:470. doi: 10.1038/s41420-023-01775-6
39. Archasappawat S, Jacques J, Lee E, and Hwang CI. Brd2 upregulation as a pan-cancer adaptive resistance mechanism to bet inhibition. bioRxiv. (2025) 30:673282. doi: 10.1101/2025.08.30.673282
40. Liu Y, Li Y, Liu S, Adeegbe DO, Christensen CL, Quinn MM, et al. Nk cells mediate synergistic antitumor effects of combined inhibition of hdac6 and bet in a sclc preclinical model. Cancer Res. (2018) 78:3709–17. doi: 10.1158/0008-5472.CAN-18-0161
41. Andrieu GP, Shafran JS, Smith CL, Belkina AC, Casey AN, Jafari N, et al. Bet protein targeting suppresses the pd-1/pd-L1 pathway in triple-negative breast cancer and elicits anti-tumor immune response. Cancer Lett. (2019) 465:45–58. doi: 10.1016/j.canlet.2019.08.013
42. Schilderink R, Bell M, Reginato E, Patten C, Rioja I, Hilbers FW, et al. Bet bromodomain inhibition reduces maturation and enhances tolerogenic properties of human and mouse dendritic cells. Mol Immunol. (2016) 79:66–76. doi: 10.1016/j.molimm.2016.09.010
43. Remke N, Bisht S, Oberbeck S, Nolting J, and Brossart P. Selective bet-bromodomain inhibition by jq1 suppresses dendritic cell maturation and antigen-specific T-cell responses. Cancer Immunol Immunother. (2021) 70:107–21. doi: 10.1007/s00262-020-02665-x
44. Gajjela BK and Zhou MM. Bromodomain inhibitors and therapeutic applications. Curr Opin Chem Biol. (2023) 75:102323. doi: 10.1016/j.cbpa.2023.102323
45. Asangani IA, Wilder-Romans K, Dommeti VL, Krishnamurthy PM, Apel IJ, Escara-Wilke J, et al. Bet bromodomain inhibitors enhance efficacy and disrupt resistance to ar antagonists in the treatment of prostate cancer. Mol Cancer Res. (2016) 14:324–31. doi: 10.1158/1541-7786.MCR-15-0472
46. Wang Q, Jia S, Wang D, Chen X, Kalvakolanu DV, Zheng H, et al. A combination of brd4 and hdac3 inhibitors synergistically suppresses glioma stem cell growth by blocking gli1/il6/stat3 signaling axis. Mol Cancer Ther. (2020) 19:2542–53. doi: 10.1158/1535-7163.MCT-20-0037
47. Mertz JA, Conery AR, Bryant BM, Sandy P, Balasubramanian S, Mele DA, et al. Targeting myc dependence in cancer by inhibiting bet bromodomains. Proc Natl Acad Sci U.S.A. (2011) 108:16669–74. doi: 10.1073/pnas.1108190108
48. Nagarajan S, Hossan T, Alawi M, Najafova Z, Indenbirken D, Bedi U, et al. Bromodomain protein brd4 is required for estrogen receptor-dependent enhancer activation and gene transcription. Cell Rep. (2014) 8:460–9. doi: 10.1016/j.celrep.2014.06.016
49. Boyson SP, Gao C, Quinn K, Boyd J, Paculova H, Frietze S, et al. Functional roles of bromodomain proteins in cancer. Cancers (Basel). (2021) 13:3606. doi: 10.3390/cancers13143606
50. Cribbs AP, Filippakopoulos P, Philpott M, Wells G, Penn H, Oerum H, et al. Dissecting the role of bet bromodomain proteins brd2 and brd4 in human nk cell function. Front Immunol. (2021) 12:626255. doi: 10.3389/fimmu.2021.626255
51. Reggiani F, Talarico G, Gobbi G, Sauta E, Torricelli F, Manicardi V, et al. Bet inhibitors drive natural killer activation in non-small cell lung cancer via brd4 and smad3. Nat Commun. (2024) 15:2567. doi: 10.1038/s41467-024-46778-8
52. Li X, Fu Y, Yang B, Guo E, Wu Y, Huang J, et al. Brd4 inhibition by azd5153 promotes antitumor immunity via depolarizing M2 macrophages. Front Immunol. (2020) 11:89. doi: 10.3389/fimmu.2020.00089
53. Belkina AC, Nikolajczyk BS, and Denis GV. Bet protein function is required for inflammation: brd2 genetic disruption and bet inhibitor jq1 impair mouse macrophage inflammatory responses. J Immunol. (2013) 190:3670–8. doi: 10.4049/jimmunol.1202838
54. Leal AS, Williams CR, Royce DB, Pioli PA, Sporn MB, and Liby KT. Bromodomain inhibitors, jq1 and I-bet 762, as potential therapies for pancreatic cancer. Cancer Lett. (2017) 394:76–87. doi: 10.1016/j.canlet.2017.02.021
55. Yan L, Tan S, Wang H, Yuan H, Liu X, Chen Y, et al. Znf687 recruits brd4-smrt complex to regulate gfi1aa during neutrophil development. Leukemia. (2024) 38:851–64. doi: 10.1038/s41375-024-02165-2
56. Cheung KL, Zhang F, Jaganathan A, Sharma R, Zhang Q, Konuma T, et al. Distinct roles of brd2 and brd4 in potentiating the transcriptional program for th17 cell differentiation. Mol Cell. (2017) 65:1068–80 e5. doi: 10.1016/j.molcel.2016.12.022
57. Milner JJ, Toma C, Quon S, Omilusik K, Scharping NE, Dey A, et al. Bromodomain protein brd4 directs and sustains cd8 T cell differentiation during infection. J Exp Med. (2021) 218:e20202512. doi: 10.1084/jem.20202512
58. Lee MB, Lee JH, Hong SH, You JS, Nam ST, Kim HW, et al. Jq1, a bet inhibitor, controls tlr4-induced il-10 production in regulatory B cells by brd4-nf-kappab axis. BMB Rep. (2017) 50:640–6. doi: 10.5483/bmbrep.2017.50.12.194
59. Kim SJ, Khadka D, and Seo JH. Interplay between solid tumors and tumor microenvironment. Front Immunol. (2022) 13:882718. doi: 10.3389/fimmu.2022.882718
60. Lanier OL, Perez-Herrero E, Andrea APD, Bahrami K, Lee E, Ward DM, et al. Immunotherapy approaches for hematological cancers. iScience. (2022) 25:105326. doi: 10.1016/j.isci.2022.105326
61. Guha P, Heatherton KR, O’Connell KP, Alexander IS, and Katz SC. Assessing the future of solid tumor immunotherapy. Biomedicines. (2022) 10:655. doi: 10.3390/biomedicines10030655
62. Lv B, Wang Y, Ma D, Cheng W, Liu J, Yong T, et al. Immunotherapy: reshape the tumor immune microenvironment. Front Immunol. (2022) 13:844142. doi: 10.3389/fimmu.2022.844142
63. Lei MML and Lee TKW. Cancer stem cells: emerging key players in immune evasion of cancers. Front Cell Dev Biol. (2021) 9:692940. doi: 10.3389/fcell.2021.692940
64. Liu Y, Lu J, Zhang Z, Zhu L, Dong S, Guo G, et al. Amlexanox, a selective inhibitor of ikbke, generates anti-tumoral effects by disrupting the hippo pathway in human glioblastoma cell lines. Cell Death Dis. (2017) 8:e3022. doi: 10.1038/cddis.2017.396
65. Tong J, Tan X, Risnik D, Gao M, Song X, Ermine K, et al. Bet protein degradation triggers dr5-mediated immunogenic cell death to suppress colorectal cancer and potentiate immune checkpoint blockade. Oncogene. (2021) 40:6566–78. doi: 10.1038/s41388-021-02041-8
66. Gallagher SJ, Mijatov B, Gunatilake D, Gowrishankar K, Tiffen J, James W, et al. Control of nf-kb activity in human melanoma by bromodomain and extra-terminal protein inhibitor I-bet151. Pigment Cell Melanoma Res. (2014) 27:1126–37. doi: 10.1111/pcmr.12282
67. Zhong L, Yang Z, Lei D, Li L, Song S, Cao D, et al. Bromodomain 4 is a potent prognostic marker associated with immune cell infiltration in breast cancer. Basic Clin Pharmacol Toxicol. (2021) 128:169–82. doi: 10.1111/bcpt.13481
68. Chen C, Liu X, Chang CY, Wang HY, and Wang RF. The interplay between T cells and cancer: the basis of immunotherapy. Genes (Basel). (2023) 14:1008. doi: 10.3390/genes14051008
69. Coenon L, Geindreau M, Ghiringhelli F, Villalba M, and Bruchard M. Natural Killer Cells at the Frontline in the Fight against Cancer. Cell Death Dis. (2024) 15:614. doi: 10.1038/s41419-024-06976-0
70. Marciscano AE and Anandasabapathy N. The role of dendritic cells in cancer and anti-tumor immunity. Semin Immunol. (2021) 52:101481. doi: 10.1016/j.smim.2021.101481
71. Kloosterman DJ and Akkari L. Macrophages at the interface of the co-evolving cancer ecosystem. Cell. (2023) 186:1627–51. doi: 10.1016/j.cell.2023.02.020
72. Liu A, Fan D, and Wang Y. The bet bromodomain inhibitor I-bet151 impairs ovarian cancer metastasis and improves antitumor immunity. Cell Tissue Res. (2018) 374:577–85. doi: 10.1007/s00441-018-2906-y
73. Smyth MJ, Cretney E, Kelly JM, Westwood JA, Street SE, Yagita H, et al. Activation of nk cell cytotoxicity. Mol Immunol. (2005) 42:501–10. doi: 10.1016/j.molimm.2004.07.034
74. Topham NJ and Hewitt EW. Natural killer cell cytotoxicity: how do they pull the trigger? Immunology. (2009) 128:7–15. doi: 10.1111/j.1365-2567.2009.03123.x
75. Fauriat C, Long EO, Ljunggren HG, and Bryceson YT. Regulation of human nk-cell cytokine and chemokine production by target cell recognition. Blood. (2010) 115:2167–76. doi: 10.1182/blood-2009-08-238469
76. Moretta L, Bottino C, Pende D, Castriconi R, Mingari MC, and Moretta A. Surface nk receptors and their ligands on tumor cells. Semin Immunol. (2006) 18:151–8. doi: 10.1016/j.smim.2006.03.002
77. Lanier LL. Nk cell recognition. Annu Rev Immunol. (2005) 23:225–74. doi: 10.1146/annurev.immunol.23.021704.115526
78. Zwirner NW and Domaica CI. Cytokine regulation of natural killer cell effector functions. Biofactors. (2010) 36:274–88. doi: 10.1002/biof.107
79. Melaiu O, Lucarini V, Cifaldi L, and Fruci D. Influence of the tumor microenvironment on nk cell function in solid tumors. Front Immunol. (2019) 10:3038. doi: 10.3389/fimmu.2019.03038
80. Nicholson SE, Keating N, and Belz GT. Natural killer cells and anti-tumor immunity. Mol Immunol. (2019) 110:40–7. doi: 10.1016/j.molimm.2017.12.002
81. Chu J, Gao F, Yan M, Zhao S, Yan Z, Shi B, et al. Natural killer cells: A promising immunotherapy for cancer. J Transl Med. (2022) 20:240. doi: 10.1186/s12967-022-03437-0
82. Wahl SM, Wen J, and Moutsopoulos NM. The kiss of death: interrupted by nk-cell close encounters of another kind. Trends Immunol. (2006) 27:161–4. doi: 10.1016/j.it.2006.02.002
83. Ghiringhelli F, Menard C, Terme M, Flament C, Taieb J, Chaput N, et al. Cd4+Cd25+ Regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner. J Exp Med. (2005) 202:1075–85. doi: 10.1084/jem.20051511
84. Holt D, Ma X, Kundu N, and Fulton A. Prostaglandin E(2) (Pge (2)) suppresses natural killer cell function primarily through the pge(2) receptor ep4. Cancer Immunol Immunother. (2011) 60:1577–86. doi: 10.1007/s00262-011-1064-9
85. Park A, Lee Y, Kim MS, Kang YJ, Park YJ, Jung H, et al. Prostaglandin E2 secreted by thyroid cancer cells contributes to immune escape through the suppression of natural killer (Nk) cell cytotoxicity and nk cell differentiation. Front Immunol. (2018) 9:1859. doi: 10.3389/fimmu.2018.01859
86. Abruzzese MP, Bilotta MT, Fionda C, Zingoni A, Soriani A, Vulpis E, et al. Inhibition of bromodomain and extra-terminal (Bet) proteins increases nkg2d ligand mica expression and sensitivity to nk cell-mediated cytotoxicity in multiple myeloma cells: role of cmyc-irf4-mir-125b interplay. J Hematol Oncol. (2016) 9:134. doi: 10.1186/s13045-016-0362-2
87. Veneziani I, Fruci D, Compagnone M, Pistoia V, Rossi P, and Cifaldi L. The bet-bromodomain inhibitor jq1 renders neuroblastoma cells more resistant to nk cell-mediated recognition and killing by downregulating ligands for nkg2d and dnam-1 receptors. Oncotarget. (2019) 10:2151–60. doi: 10.18632/oncotarget.26736
88. Lu C, Liu Y, Ali NM, Zhang B, and Cui X. The role of innate immune cells in the tumor microenvironment and research progress in anti-tumor therapy. Front Immunol. (2022) 13:1039260. doi: 10.3389/fimmu.2022.1039260
89. Li C, Xu X, Wei S, Jiang P, Xue L, Wang J, et al. Tumor-associated macrophages: potential therapeutic strategies and future prospects in cancer. J Immunother Cancer. (2021) 9:e001341. doi: 10.1136/jitc-2020-001341
90. Lin HJ, Liu Y, Caroland K, and Lin J. Polarization of cancer-associated macrophages maneuver neoplastic attributes of pancreatic ductal adenocarcinoma. Cancers (Basel). (2023) 15:9507. doi: 10.3390/cancers15133507
91. Yin M, Guo Y, Hu R, Cai WL, Li Y, Pei S, et al. Potent brd4 inhibitor suppresses cancer cell-macrophage interaction. Nat Commun. (2020) 11:1833. doi: 10.1038/s41467-020-15290-0
92. Radharani NNV, Yadav AS, Nimma R, Kumar TVS, Bulbule A, Chanukuppa V, et al. Tumor-associated macrophage derived il-6 enriches cancer stem cell population and promotes breast tumor progression via stat-3 pathway. Cancer Cell Int. (2022) 22:122. doi: 10.1186/s12935-022-02527-9
93. Wei C, Yang C, Wang S, Shi D, Zhang C, Lin X, et al. Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis. Mol Cancer. (2019) 18:64. doi: 10.1186/s12943-019-0976-4
94. Wu Y, Jennings NB, Sun Y, Dasari SK, Bayraktar E, Corvigno S, et al. Targeting ccr2(+) macrophages with bet inhibitor overcomes adaptive resistance to anti-vegf therapy in ovarian cancer. J Cancer Res Clin Oncol. (2022) 148:803–21. doi: 10.1007/s00432-021-03885-z
95. Wang S, Wang J, Chen Z, Luo J, Guo W, Sun L, et al. Targeting M2-like tumor-associated macrophages is a potential therapeutic approach to overcome antitumor drug resistance. NPJ Precis Oncol. (2024) 8:31. doi: 10.1038/s41698-024-00522-z
96. Qiao J, Chen Y, Mi Y, Jin H, Wang L, Huang T, et al. Macrophages confer resistance to bet inhibition in triple-negative breast cancer by upregulating ikbke. Biochem Pharmacol. (2020) 180:114126. doi: 10.1016/j.bcp.2020.114126
97. Olson BM, Chaudagar K, Bao R, Saha SS, Hong C, Li M, et al. Bet inhibition sensitizes immunologically cold rb-deficient prostate cancer to immune checkpoint blockade. Mol Cancer Ther. (2023) 22:751–64. doi: 10.1158/1535-7163.MCT-22-0369
98. Erkes DA, Rosenbaum SR, Field CO, Chervoneva I, Villanueva J, and Aplin AE. Plx3397 inhibits the accumulation of intra-tumoral macrophages and improves bromodomain and extra-terminal inhibitor efficacy in melanoma. Pigment Cell Melanoma Res. (2020) 33:372–7. doi: 10.1111/pcmr.12845
99. Leal AS and Liby KT. The brd4 inhibitor I-bet-762 reduces ho-1 expression in macrophages and the pancreas of mice. Int J Mol Sci. (2024) 25:9985. doi: 10.3390/ijms25189985
100. Chen X, Jiang Q, Ren L, Ren H, Xu H, Wang J, et al. Bet proteins inhibitor jq1 impairs gm-csf-promoted peritoneal macrophage self-renewal and il-4-induced alternative polarization. Int Immunopharmacol. (2023) 124:110942. doi: 10.1016/j.intimp.2023.110942
101. Chen H, Bian A, Yang LF, Yin X, Wang J, Ti C, et al. Targeting stat3 by a small molecule suppresses pancreatic cancer progression. Oncogene. (2021) 40:1440–57. doi: 10.1038/s41388-020-01626-z
102. Wang C, Kong L, Kim S, Lee S, Oh S, Jo S, et al. The role of il-7 and il-7r in cancer pathophysiology and immunotherapy. Int J Mol Sci. (2022) 23:10412. doi: 10.3390/ijms231810412
103. Chung YC, Chen SJ, Huang CC, Liu WC, Lai MT, Kao TY, et al. Tocilizumab exerts anti-tumor effects on colorectal carcinoma cell xenografts corresponding to expression levels of interleukin-6 receptor. Pharm (Basel). (2024) 17:127. doi: 10.3390/ph17010127
104. Zhang M, Qin H, Wu Y, and Gao Q. Complex role of neutrophils in the tumor microenvironment: an avenue for novel immunotherapies. Cancer Biol Med. (2024) 21:849–63. doi: 10.20892/j.issn.2095-3941.2024.0192
105. Aroca-Crevillen A, Vicanolo T, Ovadia S, and Hidalgo A. Neutrophils in physiology and pathology. Annu Rev Pathol. (2024) 19:227–59. doi: 10.1146/annurev-pathmechdis-051222-015009
106. Ng MSF, Kwok I, Tan L, Shi C, Cerezo-Wallis D, Tan Y, et al. Deterministic reprogramming of neutrophils within tumors. Science. (2024) 383:eadf6493. doi: 10.1126/science.adf6493
107. Shaul ME and Fridlender ZG. Tumour-associated neutrophils in patients with cancer. Nat Rev Clin Oncol. (2019) 16:601–20. doi: 10.1038/s41571-019-0222-4
108. Jaillon S, Ponzetta A, Di Mitri D, Santoni A, Bonecchi R, and Mantovani A. Neutrophil diversity and plasticity in tumour progression and therapy. Nat Rev Cancer. (2020) 20:485–503. doi: 10.1038/s41568-020-0281-y
109. Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, et al. Polarization of tumor-associated neutrophil phenotype by tgf-beta: “N1” Versus “N2” Tan. Cancer Cell. (2009) 16:183–94. doi: 10.1016/j.ccr.2009.06.017
110. Coffelt SB, Wellenstein MD, and de Visser KE. Neutrophils in cancer: neutral no more. Nat Rev Cancer. (2016) 16:431–46. doi: 10.1038/nrc.2016.52
111. Manni ML, Mandalapu S, Salmeron A, Lora JM, Kolls JK, and Alcorn JF. Bromodomain and extra-terminal protein inhibition attenuates neutrophil-dominant allergic airway disease. Sci Rep. (2017) 7:43139. doi: 10.1038/srep43139
112. Reid S, Fine N, Bhosle VK, Zhou J, John R, Glogauer M, et al. Inhibition of brd4 reduces neutrophil activation and adhesion to the vascular endothelium following ischemia reperfusion injury. Int J Mol Sci. (2020) 21:9620. doi: 10.3390/ijms21249620
113. Xiong S, Dong L, and Cheng L. Neutrophils in cancer carcinogenesis and metastasis. J Hematol Oncol. (2021) 14:173. doi: 10.1186/s13045-021-01187-y
114. Janssens S, Rennen S, and Agostinis P. Decoding immunogenic cell death from a dendritic cell perspective. Immunol Rev. (2024) 321:350–70. doi: 10.1111/imr.13301
115. Steinman RM. Decisions about dendritic cells: past, present, and future. Annu Rev Immunol. (2012) 30:1–22. doi: 10.1146/annurev-immunol-100311-102839
116. Schlitzer A, McGovern N, and Ginhoux F. Dendritic cells and monocyte-derived cells: two complementary and integrated functional systems. Semin Cell Dev Biol. (2015) 41:9–22. doi: 10.1016/j.semcdb.2015.03.011
117. Demoulin S, Herfs M, Delvenne P, and Hubert P. Tumor Microenvironment Converts Plasmacytoid Dendritic Cells into Immunosuppressive/Tolerogenic Cells: Insight into the Molecular Mechanisms. J Leukoc Biol. (2013) 93:343–52. doi: 10.1189/jlb.0812397
118. Chen L, Azuma T, Yu W, Zheng X, Luo L, and Chen L. B7-H1 maintains the polyclonal T cell response by protecting dendritic cells from cytotoxic T lymphocyte destruction. Proc Natl Acad Sci U.S.A. (2018) 115:3126–31. doi: 10.1073/pnas.1722043115
119. Toniolo PA, Liu S, Yeh JE, Moraes-Vieira PM, Walker SR, Vafaizadeh V, et al. Inhibiting stat5 by the bet bromodomain inhibitor jq1 disrupts human dendritic cell maturation. J Immunol. (2015) 194:3180–90. doi: 10.4049/jimmunol.1401635
120. Liu S, Walker SR, Nelson EA, Cerulli R, Xiang M, Toniolo PA, et al. Targeting stat5 in hematologic Malignancies through inhibition of the bromodomain and extra-terminal (Bet) bromodomain protein brd2. Mol Cancer Ther. (2014) 13:1194–205. doi: 10.1158/1535-7163.MCT-13-0341
121. Pinz S, Unser S, Buob D, Fischer P, Jobst B, and Rascle A. Deacetylase inhibitors repress stat5-mediated transcription by interfering with bromodomain and extra-terminal (Bet) protein function. Nucleic Acids Res. (2015) 43:3524–45. doi: 10.1093/nar/gkv188
122. Pinz S, Unser S, and Rascle A. Signal transducer and activator of transcription stat5 is recruited to C-myc super-enhancer. BMC Mol Biol. (2016) 17:10. doi: 10.1186/s12867-016-0063-y
123. Chaudhary B and Elkord E. Regulatory T cells in the tumor microenvironment and cancer progression: role and therapeutic targeting. Vaccines (Basel). (2016) 4:28. doi: 10.3390/vaccines4030028
124. Chen Y, Yu D, Qian H, Shi Y, and Tao Z. Cd8(+) T cell-based cancer immunotherapy. J Transl Med. (2024) 22:394. doi: 10.1186/s12967-024-05134-6
125. Pan Y, Zhou H, Sun Z, Zhu Y, Zhang Z, Han J, et al. Regulatory T cells in solid tumor immunotherapy: effect, mechanism and clinical application. Cell Death Dis. (2025) 16:277. doi: 10.1038/s41419-025-07544-w
126. Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, and Anderson AC. Targeting tim-3 and pd-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med. (2010) 207:2187–94. doi: 10.1084/jem.20100643
127. Thommen DS, Schreiner J, Muller P, Herzig P, Roller A, Belousov A, et al. Progression of lung cancer is associated with increased dysfunction of T cells defined by coexpression of multiple inhibitory receptors. Cancer Immunol Res. (2015) 3:1344–55. doi: 10.1158/2326-6066.CIR-15-0097
128. Shayan G, Srivastava R, Li J, Schmitt N, Kane LP, and Ferris RL. Adaptive resistance to anti-pd1 therapy by tim-3 upregulation is mediated by the pi3k-akt pathway in head and neck cancer. Oncoimmunology. (2017) 6:e1261779. doi: 10.1080/2162402X.2016.1261779
129. Schnell A, Bod L, Madi A, and Kuchroo VK. The yin and yang of co-inhibitory receptors: toward anti-tumor immunity without autoimmunity. Cell Res. (2020) 30:285–99. doi: 10.1038/s41422-020-0277-x
130. Farrag M, Ibrahim E, Abdelwahab H, Elsergany A, and Elhadidy T. Pdl-1 expression in lung carcinoma and its correlation with clinicopathological and prognostic characteristics. J Immunoassay Immunochem. (2021) 42:679–90. doi: 10.1080/15321819.2021.1938606
131. Helmy DO, Khattab F, Hegazy AE, and Sabry RM. Immunohistochemical expression of immune check point protein pdl-1 in hepatocellular carcinoma denotes its prognostic significance and association with survival. J Immunoassay Immunochem. (2023) 44:213–28. doi: 10.1080/15321819.2022.2137810
132. Constantinidou A, Alifieris C, and Trafalis DT. Targeting programmed cell death -1 (Pd-1) and ligand (Pd-L1): A new era in cancer active immunotherapy. Pharmacol Ther. (2019) 194:84–106. doi: 10.1016/j.pharmthera.2018.09.008
133. Bayraktar S, Batoo S, Okuno S, and Gluck S. Immunotherapy in breast cancer. J Carcinog. (2019) 18:2. doi: 10.4103/jcar.JCar_2_19
134. Tahir IM, Rauf A, Mehboob H, Sadaf S, Alam MS, Kalsoom F, et al. Prognostic significance of programmed death-1 and programmed death ligand-1 proteins in breast cancer. Hum Antibodies. (2022) 30:131–50. doi: 10.3233/HAB-220001
135. Samanta D, Park Y, Ni X, Li H, Zahnow CA, Gabrielson E, et al. Chemotherapy induces enrichment of cd47(+)/cd73(+)/pdl1(+) immune evasive triple-negative breast cancer cells. Proc Natl Acad Sci U.S.A. (2018) 115:E1239–E48. doi: 10.1073/pnas.1718197115
136. DhatChinamoorthy K, Colbert JD, and Rock KL. Cancer immune evasion through loss of mhc class I antigen presentation. Front Immunol. (2021) 12:636568. doi: 10.3389/fimmu.2021.636568
137. Ni XY, Sui HX, Liu Y, Ke SZ, Wang YN, and Gao FG. Tgf-beta of lung cancer microenvironment upregulates B7h1 and gitrl expression in dendritic cells and is associated with regulatory T cell generation. Oncol Rep. (2012) 28:615–21. doi: 10.3892/or.2012.1822
138. Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, et al. Pd-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. (2009) 206:3015–29. doi: 10.1084/jem.20090847
139. Zheng Y, Chen Z, Han Y, Han L, Zou X, Zhou B, et al. Immune suppressive landscape in the human esophageal squamous cell carcinoma microenvironment. Nat Commun. (2020) 11:6268. doi: 10.1038/s41467-020-20019-0
140. Zhu H, Bengsch F, Svoronos N, Rutkowski MR, Bitler BG, Allegrezza MJ, et al. Bet bromodomain inhibition promotes anti-tumor immunity by suppressing pd-L1 expression. Cell Rep. (2016) 16:2829–37. doi: 10.1016/j.celrep.2016.08.032
141. Mao W, Ghasemzadeh A, Freeman ZT, Obradovic A, Chaimowitz MG, Nirschl TR, et al. Immunogenicity of prostate cancer is augmented by bet bromodomain inhibition. J Immunother Cancer. (2019) 7:277. doi: 10.1186/s40425-019-0758-y
142. Wang M, Zhao L, Tong D, Yang L, Zhu H, Li Q, et al. Bet bromodomain inhibitor jq1 promotes immunogenic cell death in tongue squamous cell carcinoma. Int Immunopharmacol. (2019) 76:105921. doi: 10.1016/j.intimp.2019.105921
143. Kagoya Y, Nakatsugawa M, Yamashita Y, Ochi T, Guo T, Anczurowski M, et al. Bet bromodomain inhibition enhances T cell persistence and function in adoptive immunotherapy models. J Clin Invest. (2016) 126:3479–94. doi: 10.1172/JCI86437
144. Wang X, Yu B, Cao B, Zhou J, Deng Y, Wang Z, et al. A chemical conjugation of jq-1 and a tlr7 agonist induces tumoricidal effects in a murine model of melanoma via enhanced immunomodulation. Int J Cancer. (2021) 148:437–47. doi: 10.1002/ijc.33222
145. Liu C, Miao X, Wang Y, Wen L, Cheng X, Kong D, et al. Bromo- and extraterminal domain protein inhibition improves immunotherapy efficacy in hepatocellular carcinoma. Cancer Sci. (2020) 111:3503–15. doi: 10.1111/cas.14588
146. Zhang Z, Zhang Q, Xie J, Zhong Z, and Deng C. Enzyme-responsive micellar jq1 induces enhanced bet protein inhibition and immunotherapy of Malignant tumors. Biomater Sci. (2021) 9:6915–26. doi: 10.1039/d1bm00724f
147. Adeegbe DO, Liu S, Hattersley MM, Bowden M, Zhou CW, Li S, et al. Bet bromodomain inhibition cooperates with pd-1 blockade to facilitate antitumor response in kras-mutant non-small cell lung cancer. Cancer Immunol Res. (2018) 6:1234–45. doi: 10.1158/2326-6066.CIR-18-0077
148. Noyes D, Bag A, Oseni S, Semidey-Hurtado J, Cen L, Sarnaik AA, et al. Tumor-associated tregs obstruct antitumor immunity by promoting T cell dysfunction and restricting clonal diversity in tumor-infiltrating cd8+ T cells. J Immunother Cancer. (2022) 10:e004605. doi: 10.1136/jitc-2022-004605
149. Hogg SJ, Vervoort SJ, Deswal S, Ott CJ, Li J, Cluse LA, et al. Bet-bromodomain inhibitors engage the host immune system and regulate expression of the immune checkpoint ligand pd-L1. Cell Rep. (2017) 18:2162–74. doi: 10.1016/j.celrep.2017.02.011
150. Adeegbe DO, Freeman GJ, and Wong K-K. Bet bromodomain inhibition synergizes with immune checkpoint blockade to facilitate anti-tumor response in a murine model of non-small cell lung cancer harboring activating kras mutation. J Immunol. (2016) 196:74.10–0. doi: 10.4049/jimmunol.196.Supp.74.10
151. Erkes DA, Field CO, Capparelli C, Tiago M, Purwin TJ, Chervoneva I, et al. The next-generation bet inhibitor, plx51107, delays melanoma growth in a cd8-mediated manner. Pigment Cell Melanoma Res. (2019) 32:687–96. doi: 10.1111/pcmr.12788
152. Bandukwala HS, Gagnon J, Togher S, Greenbaum JA, Lamperti ED, Parr NJ, et al. Selective inhibition of cd4+ T-cell cytokine production and autoimmunity by bet protein and C-myc inhibitors. Proc Natl Acad Sci U.S.A. (2012) 109:14532–7. doi: 10.1073/pnas.1212264109
153. Mele DA, Salmeron A, Ghosh S, Huang HR, Bryant BM, and Lora JM. Bet bromodomain inhibition suppresses th17-mediated pathology. J Exp Med. (2013) 210:2181–90. doi: 10.1084/jem.20130376
154. Hu X, Schewitz-Bowers LP, Lait PJP, Copland DA, Stimpson ML, Li JJ, et al. The bromodomain and extra-terminal protein inhibitor otx015 suppresses T helper cell proliferation and differentiation. Curr Mol Med. (2018) 18:594–601. doi: 10.2174/1566524019666190126112238
155. Cheung K, Lu G, Sharma R, Vincek A, Zhang R, Plotnikov AN, et al. Bet N-terminal bromodomain inhibition selectively blocks th17 cell differentiation and ameliorates colitis in mice. Proc Natl Acad Sci U.S.A. (2017) 114:2952–7. doi: 10.1073/pnas.1615601114
156. Copsel SN, Lightbourn CO, Barreras H, Lohse I, Wolf D, Bader CS, et al. Bet bromodomain inhibitors which permit treg function enable a combinatorial strategy to suppress gvhd in pre-clinical allogeneic hsct. Front Immunol. (2018) 9:3104. doi: 10.3389/fimmu.2018.03104
157. Largeot A, Pagano G, Gonder S, Moussay E, and Paggetti J. The B-side of cancer immunity: the underrated tune. Cells. (2019) 8:449. doi: 10.3390/cells8050449
158. Khan AR, Hams E, Floudas A, Sparwasser T, Weaver CT, and Fallon PG. Pd-L1hi B cells are critical regulators of humoral immunity. Nat Commun. (2015) 6:5997. doi: 10.1038/ncomms6997
159. Sarvaria A, Madrigal JA, and Saudemont A. B cell regulation in cancer and anti-tumor immunity. Cell Mol Immunol. (2017) 14:662–74. doi: 10.1038/cmi.2017.35
160. Dalloul Z, Best M, Chenuet P, Dalloul I, Le Noir S, Togbe D, et al. Bromodomain and extraterminal (Bet) protein inhibition of igg/ige production in murine B cells is counter-balanced by a strong th2 bias. Clin Transl Immunol. (2021) 10:e1280. doi: 10.1002/cti2.1280
161. Belkina AC, Blanton WP, Nikolajczyk BS, and Denis GV. The double bromodomain protein brd2 promotes B cell expansion and mitogenesis. J Leukoc Biol. (2014) 95:451–60. doi: 10.1189/jlb.1112588
162. Ocana A, Nieto-Jimenez C, and Pandiella A. Bet inhibitors as novel therapeutic agents in breast cancer. Oncotarget. (2017) 8:71285–91. doi: 10.18632/oncotarget.19744
163. Walsh L, Haley KE, Moran B, Mooney B, Tarrant F, Madden SF, et al. Bet inhibition as a rational therapeutic strategy for invasive lobular breast cancer. Clin Cancer Res. (2019) 25:7139–50. doi: 10.1158/1078-0432.CCR-19-0713
164. Gilan O, Rioja I, Knezevic K, Bell MJ, Yeung MM, Harker NR, et al. Selective targeting of bd1 and bd2 of the bet proteins in cancer and immunoinflammation. Science. (2020) 368:387–94. doi: 10.1126/science.aaz8455
165. Jung M, Gelato KA, Fernandez-Montalvan A, Siegel S, and Haendler B. Targeting bet bromodomains for cancer treatment. Epigenomics. (2015) 7:487–501. doi: 10.2217/epi.14.91
166. Quintela M, James DW, Pociute A, Powell L, Edwards K, Coombes Z, et al. Bromodomain inhibitor I-bet858 triggers a unique transcriptional response coupled to enhanced DNA damage, cell cycle arrest and apoptosis in high-grade ovarian carcinoma cells. Clin Epigenet. (2023) 15:63. doi: 10.1186/s13148-023-01477-x
167. Sharifhoseini A, Heshmati M, Soltani A, Entezam M, Shirzad H, Sedehi M, et al. Effects of bromodomain and extra-terminal inhibitor jq1 and interleukin-6 on breast cancer cells. Mol Biol Rep. (2023) 50:8319–28. doi: 10.1007/s11033-023-08718-5
168. Ma L, Zhang X, Xu S, Dai J, Huang Z, Ruan Z, et al. Nhwd-870 suppresses tumor proliferation via the brd4/strada/ccnd1 axis in small cell lung cancer. Lung Cancer. (2025) 210:108841. doi: 10.1016/j.lungcan.2025.108841
169. Colardo M, Gargano D, Russo M, Petraroia M, Pensabene D, D’Alessandro G, et al. Bromodomain and extraterminal domain (Bet) protein inhibition hinders glioblastoma progression by inducing autophagy-dependent differentiation. Int J Mol Sci. (2023) 24:7017. doi: 10.3390/ijms24087017
170. Miyashita Y, Tajima K, Izumi K, Matsumoto N, Hayakawa D, Nakamura IT, et al. Novel approach to overcome osimertinib resistance using bromodomain and extra-terminal domain inhibitors. Cancer Sci. (2025) 116:1392–404. doi: 10.1111/cas.70032
171. Li Z, Duan J, Liu Z, Li W, Mai Y, Fu H, et al. A triple-mode strategy on jq1-loaded nanoplatform for superior antitumor therapy in pancreatic cancer. Mater Today Bio. (2025) 32:101696. doi: 10.1016/j.mtbio.2025.101696
172. Zhang Y, Pan Z, Chen C, Tan Y, Wang X, Wang L, et al. Design, synthesis and anti-ovarian cancer activities of thieno[2,3-D]Pyrimidine based chimeric brd4 inhibitor/nitric oxide-donator. Eur J Med Chem. (2023) 246:114970. doi: 10.1016/j.ejmech.2022.114970
173. Cheng ML, Huang Y, Luong N, LoPiccolo J, Nishino M, Sholl LM, et al. Exceptional response to bromodomain and extraterminal domain inhibitor therapy with bms-986158 in brd4-nutm1 nut carcinoma harboring a brd4 splice site mutation. JCO Precis Oncol. (2023) 7:e2200633. doi: 10.1200/PO.22.00633
174. Kim S, Jeon SH, Han MG, Kang MH, and Kim IA. Brd4 inhibition enhances the antitumor effects of radiation therapy in a murine breast cancer model. Int J Mol Sci. (2023) 24:10413. doi: 10.3390/ijms241713062
175. Watanabe J, Clutter MR, Gullette MJ, Sasaki T, Uchida E, Kaur S, et al. Bet bromodomain inhibition potentiates radiosensitivity in models of H3k27-altered diffuse midline glioma. J Clin Invest. (2024) 134:e174794. doi: 10.1172/JCI174794
176. Fan X, Yang Y, Li X, Yu L, Wang Y, Wang Z, et al. Brd4 inhibition sensitizes glioblastoma to radiotherapy by suppressing super-enhancer-driven col1a1. Oncogene. (2025) 44:4462–74. doi: 10.1038/s41388-025-03596-6
177. Liukaityte R, Stenberg VY, Kleinauskas A, Juzenas P, Urbanucci A, and Juzeniene A. Combination of psma targeting alpha-emitting radioligand [(212)Pb]Pb-ab001 with bet bromodomain inhibitors in in vitro prostate cancer models. Med Oncol. (2025) 42:362. doi: 10.1007/s12032-025-02925-9
178. Liang H, Yang C, Zeng R, Song Y, Wang J, Xiong W, et al. Targeting cbx3 with a dual bet/plk1 inhibitor enhances the antitumor efficacy of cdk4/6 inhibitors in prostate cancer. Adv Sci (Weinh). (2023) 10:e2302368. doi: 10.1002/advs.202302368
179. Zeng F, Li Y, Meng Y, Sun H, He Y, Yin M, et al. Bet inhibitors synergize with sunitinib in melanoma through gdf15 suppression. Exp Mol Med. (2023) 55:364–76. doi: 10.1038/s12276-023-00936-y
180. Chi S, Wei F, Li Y, Yu L, Ma C, Fang Y, et al. Bet inhibitor and cdk4/6 inhibitor synergistically inhibit breast cancer by suppressing brd4 stability and DNA damage repair. Transl Oncol. (2025) 51:102212. doi: 10.1016/j.tranon.2024.102212
181. Feng B, Yu H, Dong X, Diaz-Holguin A, Antolin AA, and Hu H. Combining data-driven and structure-based approaches in designing dual parp1-brd4 inhibitors for breast cancer treatment. J Chem Inf Model. (2024) 64:7725–42. doi: 10.1021/acs.jcim.4c01421
182. Peng X, Huang X, Zhang S, Zhang N, Huang S, Wang Y, et al. Sequential inhibition of parp and bet as a rational therapeutic strategy for glioblastoma. Adv Sci (Weinh). (2024) 11:e2307747. doi: 10.1002/advs.202307747
183. Hu R, Hou H, Li Y, Zhang M, Li X, Chen Y, et al. Combined bet and mek inhibition synergistically suppresses melanoma by targeting yap1. Theranostics. (2024) 14:593–607. doi: 10.7150/thno.85437
184. Li B, Chen Y, Wang S, Jin B, Yang J, Niu Q, et al. Discovery of 4,5-dihydro-benzo[G]Indazole-based hydroxamic acids as hdac3/brd4 dual inhibitors and anti-tumor agents. Eur J Med Chem. (2025) 285:117230. doi: 10.1016/j.ejmech.2024.117230
185. Tseng HY, Alavi S, Gallagher S, McGuire HM, Hersey P, Al Emran A, et al. Bet inhibition sensitizes innate checkpoint inhibitor resistant melanoma to anti-ctla-4 treatment. Pigment Cell Melanoma Res. (2024) 37:744–51. doi: 10.1111/pcmr.13174
186. Aleckovic M, Li Z, Zhou N, Qiu X, Lulseged B, Foidart P, et al. Combination therapies to improve the efficacy of immunotherapy in triple-negative breast cancer. Mol Cancer Ther. (2023) 22:1304–18. doi: 10.1158/1535-7163.MCT-23-0303
187. Jiang Z, Cai G, Liu H, Liu L, Huang R, Nie X, et al. A combination of a tlr7/8 agonist and an epigenetic inhibitor suppresses triple-negative breast cancer through triggering anti-tumor immune. J Nanobiotechnol. (2024) 22:296. doi: 10.1186/s12951-024-02525-1
188. Slavic Obradovic K, Ebner F, Artemov AV, Miotto M, Traexler PE, Jacob R, et al. Combining bet inhibition with smac mimetics restricts tumor growth and triggers immune surveillance in preclinical cancer models. Cell Rep Med. (2025) 6:102313. doi: 10.1016/j.xcrm.2025.102313
189. Wang W, Li X, Hu R, Dong L, Pei S, Jin L, et al. Bet inhibitor in combination with bcg vaccine enhances antitumor efficacy and orchestrates T cell reprogramming for melanoma. Cell Rep Med. (2025) 6:101995. doi: 10.1016/j.xcrm.2025.101995
190. Ortega-Bertran S, Fernandez-Rodriguez J, Magallon-Lorenz M, Zhang X, Creus-Bachiller E, Diazgranados AP, et al. Triple combination of mek, bet, and cdk inhibitors significantly reduces human Malignant peripheral nerve sheath tumors in mouse models. Clin Cancer Res. (2025) 31:907–20. doi: 10.1158/1078-0432.CCR-24-2807
191. Bollmann LM, Lange F, Hamacher A, Biermann L, Schaker-Hubner L, Hansen FK, et al. Triple combination of entinostat, a bromodomain inhibitor, and cisplatin is a promising treatment option for bladder cancer. Cancers (Basel). (2024) 16:3374. doi: 10.3390/cancers16193374
192. Senapati J, Fiskus WC, Daver N, Wilson NR, Ravandi F, Garcia-Manero G, et al. Phase I results of bromodomain and extra-terminal inhibitor plx51107 in combination with azacitidine in patients with relapsed/refractory myeloid Malignancies. Clin Cancer Res. (2023) 29:4352–60. doi: 10.1158/1078-0432.CCR-23-1429
193. Zhang Y, Yin Q, Zhao B, Liu F, Li S, Cai J, et al. Tqb3617, a bromodomain and extra-terminal inhibitor, in patients with relapsed or refractory lymphoma: A multicenter, phase 1 trial. Med. (2025), 100893. doi: 10.1016/j.medj.2025.100893
194. Hamilton EP, Wang JS, Oza AM, Patel MR, Ulahannan SV, Bauer T, et al. First-in-human study of azd5153, a small-molecule inhibitor of bromodomain protein 4, in patients with relapsed/refractory Malignant solid tumors and lymphoma. Mol Cancer Ther. (2023) 22:1154–65. doi: 10.1158/1535-7163.MCT-23-0065
195. Duska LR, Zamarin D, Hamilton E, Oza A, Fleming G, Spira A, et al. Phase iia study of plx2853 in gynecologic cancers with known arid1a mutation and phase ib/iia study of plx2853/carboplatin in platinum-resistant epithelial ovarian cancer. JCO Precis Oncol. (2023) 7:e2300235. doi: 10.1200/PO.23.00235
196. Marbach D, Brouer-Visser J, Brennan L, Wilson S, Davydov II, Staedler N, et al. Immune modulation in solid tumors: A phase 1b study of ro6870810 (Bet inhibitor) and atezolizumab (Pd-L1 inhibitor). BMC Cancer. (2025) 25:500. doi: 10.1186/s12885-025-13851-4
197. Lauer UM, Awada A, Postel-Vinay S, Shapiro GI, Thieblemont C, Piha-Paul SA, et al. Final results from the phase ia/ib study of the novel bromodomain and extra-terminal domain inhibitor, bi 894999, in patients with advanced solid tumors or diffuse large B-cell lymphoma. ESMO Open. (2025) 10:104499. doi: 10.1016/j.esmoop.2025.104499
198. Lai X, Stiff A, Duggan M, Wesolowski R, Carson WE 3rd, and Friedman A. Modeling combination therapy for breast cancer with bet and immune checkpoint inhibitors. Proc Natl Acad Sci U.S.A. (2018) 115:5534–9. doi: 10.1073/pnas.1721559115
199. Castro F, Cardoso AP, Goncalves RM, Serre K, and Oliveira MJ. Interferon-gamma at the crossroads of tumor immune surveillance or evasion. Front Immunol. (2018) 9:847. doi: 10.3389/fimmu.2018.00847
200. Flood BA, Higgs EF, Li S, Luke JJ, and Gajewski TF. Sting pathway agonism as a cancer therapeutic. Immunol Rev. (2019) 290:24–38. doi: 10.1111/imr.12765
201. Wu W, Chia T, Lu J, Li X, Guan J, Li Y, et al. Il-2ralpha-biased agonist enhances antitumor immunity by invigorating tumor-infiltrating cd25(+)Cd8(+) T cells. Nat Cancer. (2023) 4:1309–25. doi: 10.1038/s43018-023-00612-0
202. Wang J, Xu Y, Rao X, Zhang R, Tang J, Zhang D, et al. Brd4-irf1 axis regulates chemoradiotherapy-induced pd-L1 expression and immune evasion in non-small cell lung cancer. Clin Transl Med. (2022) 12:e718. doi: 10.1002/ctm2.718
203. Deng J, Zhao S, Zhang X, Jia K, Wang H, Zhou C, et al. Ox40 (Cd134) and ox40 ligand, important immune checkpoints in cancer. Onco Targets Ther. (2019) 12:7347–53. doi: 10.2147/OTT.S214211
204. Kim AMJ, Nemeth MR, and Lim SO. 4-1bb: A promising target for cancer immunotherapy. Front Oncol. (2022) 12:968360. doi: 10.3389/fonc.2022.968360
Keywords: B cells, BET inhibitors (BETi), bromodomain and extra-terminal proteins (BET proteins), NK cells, T cells, tumor-associated macrophages (TAMs)
Citation: Sharma D, Bushnell GG, Kalman AP, Hutchens CM and Burness ML (2026) Bromodomain and extra-terminal proteins in solid tumors: regulators of immune microenvironment and emerging therapeutic targets. Front. Immunol. 16:1727365. doi: 10.3389/fimmu.2025.1727365
Received: 17 October 2025; Accepted: 15 December 2025; Revised: 05 December 2025;
Published: 09 January 2026.
Edited by:
Giovanna Chiorino, Fondazione Edo ed Elvo Tempia, ItalyReviewed by:
Francesca Reggiani, IRCCS Local Health Authority of Reggio Emilia, ItalyTiziana Servidei, Agostino Gemelli University Polyclinic (IRCCS), Italy
Copyright © 2026 Sharma, Bushnell, Kalman, Hutchens and Burness. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Monika L. Burness, bWJ1cm5lc3NAbWVkLnVtaWNoLmVkdQ==