Dendritic cells (DCs) represent a subset of innate immune cells that play a pivotal role in initiating antigen-specific immune responses and the maintenance of tolerance(Gardner et al., 2020). Previously, Tiphanie et al. demonstrated the indispensable role of JunB in the production of proinflammatory cytokines IL-6, IL-12 and TNF-α in LPS-stimulated DCs derived from mouse primary bone marrow (Gomard et al., 2010). Mechanically, optimal transcription of these cytokines relies on the synergistic cooperation between JunB and NF-κB, thereby suggesting a regulatory pathway where one transcription factor induces the expression of the other before engaging in cooperative actions (Gomard et al., 2010). Intriguingly, in unstimulated DCs, the JunB gene remains transcriptionally inactive and is organized within a compact chromatin loop, facilitating spatial proximity between its upstream promoter region and downstream enhancer region (Salem et al., 2013). Generally, DCs can be classified into two distinct branches, conventional (cDCs) and plasmacytoid DCs (pDCs) based on their unique transcriptional, functional, and cell surface phenotypes. cDCs can be further subdivided into two subsets, cDC1 which is specialized in cross-presentation, and cDC2 that plays a crucial role in the induction of Th2 and Th17 immunity (Gardner et al., 2020). Notably, the deletion of JunB and c-Jun in DC progenitors remarkably reduced the CD8α cDC1population, resulting in impaired TLR activation and antigen cross-presentation. However, other cDC subsets, such as CD103 cDC1, remained unaffected. These findings suggest that JunB and c-Jun are essential for diversification, function, and identity maintenance of CD8α cDC1 (Novoszel et al., 2021). Therefore, the function of JunB in promoting inflammatory cytokine secretion in DCs is contingent upon the presence of inflammatory milieu, and activated JunB may exert a pivotal regulatory role in cDC1 cell differentiation and immune defense. Given the crucial role of cDCs in anti-tumor immune response (Marciscano and Anandasabapathy, 2021), comprehending the involvement of transcription factors in cDC differentiation and activity is imperative for the development of effective antitumor targets.

Additionally, JunB regulates the polarization and cytokine secretion of macrophages, which are tissue tissue-resident phagocytes of the innate immune system responsible for detecting and restraining infected microorganisms and initiating an immune response. Intriguingly, macrophages with different phenotypes play roles in inflammation and immunoregulation at different stages of the immune response. Traditionally, based on their surface markers or distinct functions, macrophages are divided into M1 (pro-inflammation) and M2 (immunoregulation) macrophages, although subsets of macrophages are complex (Wynn and Vannella, 2016). Initially, the researchers found that JunB was significantly upregulated in macrophages upon stimulation with IL-6, LPS and bovine type I collagen in serum (Oritani et al., 1992; Cho et al., 2002; Frazier-Jessen et al., 2002). Fontana et al. constructed a network regulating macrophages and identified a correlation between JunB and Il1b. Myeloid-restricted knockout of JunB led to a remarkable decrease of Il1b mRNA and IL-1β protein in BMDMs treated with LPS or LPS plus ATP. Further experiments demonstrated that JunB could regulate macrophage responses stimulated by various immunostimulatory ligands, including poly (I:C), imiquimod, CpG DNA and cyclic-di-GMP (Fontana et al., 2015b). Noteworthily, JunB exerted a significant impact on the polarization of M1 and M2 macrophages, while exhibiting no discernible influence on macrophage proliferation, differentiation, and phagocytosis (Fontana et al., 2015b). However, this study exclusively evaluated the impact of JunB on macrophage polarization in vitro. Their subsequent work found that mice deficient in JunB specifically within myeloid cells exhibited resistance to Plasmodium berghei-elicited type 1 immune activation, as evidenced by diminished cerebral pathology and improved survival. Additionally, these mice also displayed reduced Nippostrongylus brasiliensis-elicited type 2 activation, characterized by decreased cytokine secretion and eosinophil recruitment alongside increased parasite burden(Fontana et al., 2015a). In general, these studies suggest that JunB plays a crucial role in macrophage-mediated immune responses. With the development of single-cell RNA sequencing (scRNA-seq) technology, more macrophage subtypes have been identified. Recently, a scRNA-seq study conducted on peripheral immune cells of patients with systemic sclerosis (SSc) revealed a novel inflammatory gene module originating from CD16⁺ monocytes, which included KLF10, PLAUR, JUNB and JUND; this module displayed the greatest discrimination compared to healthy control group(Kobayashi et al., 2021). It is intriguing to consider whether JunB plays a role in determining the fate of additional macrophage subtypes. Furthermore, the observation that JunB modulates macrophage activity within the TME by transcriptionally regulating chemokine secretion from tumor cells provides valuable insight, as M2 macrophages infiltration exacerbates solid tumor progression (Arakaki et al., 2016; Cassetta and Pollard, 2018). This suggests that JunB may serve as a crucial regulator in the macrophage polarization within the tumor microenvironment (TME).

Similar to macrophages, neutrophils are skilled phagocytes that digest and destroy invading pathogens. Besides, neutrophils play an immunoregulatory role in both the innate and adaptive systems due to their capacity in producing pro-inflammatory or immune-suppressive cytokines. However, when over-activated, their strong immune response can cause collateral damage, which may lead to the occurrence of immune diseases (Liew and Kubes, 2019). Recent studies have unveiled that JunB functions as a lineage-determining transcriptional factor that plays a crucial role in promoting neutrophil cell survival and establishing their effector function repertoire through transcriptionally accessible. Upon activation, JunB becomes activated and subsequently occupies the promoter regions of target genes, thereby facilitating the effector of neutrophils (Khoyratty et al., 2021). Intriguingly, it has been reported that PU.1 (encoded by Spi1 gene) recruits HDAC1 to repress the expression of immune-related genes, leading to a reduction in AP-1-binding motif accessibility within enhancers. Notably, among all AP-1 transcription factors present in activated neutrophils, JunB is found to be the most abundant transcript; however, PU.1 prevents JunB from accessing to enhancers in immature neutrophils (Fischer et al., 2019). Thus, the interaction between PU.1, JunB and HADC1 plays a crucial role in regulating neutrophil activities. Subsequently, Khoyratty et al. conducted transcriptional and chromatin analyses of neutrophils during acute inflammation and demonstrated that JunB is capable of driving various effector responses in neutrophils, such as enhancing reactive oxygen species (ROS) production, bacterial killing and NET formation (Khoyratty et al., 2021). In the mouse model of acute myocardial infarction, JunB knockout in neutrophils attenuated pathological inflammation (Khoyratty et al., 2021). Overall, under normal conditions, PU.1 controls JunB; however, during inflammation, the repressive effect of PU.1 on JunB is abrogated, leading to activation of JunB and subsequent enhancement of transcriptional activity that promotes neutrophil-mediated immune processes. Nevertheless, stromal loss of JunB was found to promote the infiltration of neutrophil in tumor metastasis (Fischer et al., 2019; Wutschka et al., 2021). The bidirectional role of JunB in immune regulation is evident as its regulatory effects on neutrophils may exhibit reversibility in other inflammatory diseases and tumor states.

In innate immune system, natural killer (NK) cells are effector cells that perform cytolysis and cytokine-producing function. Their specialized receptors, such as NKG2D, monitor infected neighboring cells by recognizing the absence of cell surface MHC (McComb et al., 2019). The binding of NKG2D (receptor) with ligand RAE-1 plays an important role in the anti-tumor immune response mediated by NK cell, γδ⁺ T and CD8⁺ T cells. Nausch et al. found that JunB knockdown enhanced cell surface expression of RAE-1 in mouse embryonic cell lines, which was helpful to enhance the killing ability of NK cells to JunB-deficient cells and IFN-γ production through NKG2D(Nausch et al., 2006). This study suggests that due to loss of JunB, the upregulation of RAE-1 can alarm immune cells to tumors or abnormal stressed cells. Inconsistently, Wang et al. found that JunB is a cofactor required for Smad4-mediated maturation, homeostasis and anti-tumor effects of NK cells by potentiating expression of granzyme B (Wang et al., 2018). In addition, Thomsen et al. found that JunB can directly bind to the promoter of IFN-γ in NK/NKT cells, promoting transcription and production of IFN-γ, and thereby aggravating acute hepatitis (Thomsen et al., 2013). These studies also suggest a biphasic role for JunB in tumor and NK cells. However, the current study is not clear whether JunB promotes or inhibits the effect of NK cells in the tumor microenvironment, and more studies are needed to prove it.

Leukemia is a series of malignant diseases of blood and bone marrow that threaten human life. Genetic abnormalities are widely known to be associated with leukemia occurrence (Juliusson and Hough, 2016). Notably, patients with acute or chronic myeloid leukemia presented low expression levels of JunB, increasing studies suggested JunB affect cell cycle and differentiation through transcriptionally activating essential genes. Transcription factor PU.1 is necessary for granulocyte monocyte differentiation during normal hematopoiesis. Knocking out terminal enhancer of PU.1 reduces the expression level of PU.1 in bone marrow by 80%, resulting in the occurrence of acute myeloid leukemia (AML) in mice (Rosenbauer et al., 2004; Rosenbauer et al., 2005). On this basis, Steidl et al. found that JunB was significantly down-regulated in PU.1 knockdown preleukemia hematopoietic stem cells. Lentivirus-mediated JunB repair can make NOD-SCID mice lose their self-renewal ability and inhibit the progress of leukemia. In addition, correlation between the down-regulation of PU.1 and JunB was confirmed by examination of AML patients. The decrease of JunB expression might be one of the causes of malignant self-renewal of HSC in AML patients (Somervaille and Cleary, 2006; Steidl et al., 2006). Deletion of two orphan nuclear receptors, Nr4a3 and Nr4a1, also led to the occurrence of AML. In Nr4a3^-/-Nr4a1^-/- mice, the expression of PU.1 was not affected, but the transcripts of c-Jun and JunB were significantly down-regulated, indicating that the downregulation of AP-1 transcription factors may contribute to the development of AML in these mice (Mullican et al., 2007). Santaguida et al. found that JunB inactivation disturbs the regulation of cell cycle and increases the proliferation of long-term repopulating HSCs (LT-HSCs) without affecting its self-renewal in vivo. JunB frequently controls the proliferation of LT-HSCs and limits the rate of myeloid progenitor cells production by maintaining proper response to Notch and TGF-β signals, partly through the transcriptional regulation of these two pathways, which are important mediators of Hes1. The deletion of JunB gene destroyed the stability of the network of genes and pathways that regulate the fate of HSC, resulting in abnormal expansion of myeloid progenitor cells, which promotes the occurrence of myeloid malignant tumors (Guzman and Jordan, 2009; Santaguida et al., 2009). Fiskus et al. found that the inhibitory effect of panobinostat (a pan-HADC inhibitor) combined with dexitabine on human AML cells was stronger than that of one of them. Mechanical studies showed dexitabine induced demethylation of JunB promoter, and panobinostat treatment mediated chromatin change of JunB promoter to increase JunB level, both of them have synergistic effects (Fiskus et al., 2009). In acute promyelocytic leukemia (APL), S-phase kinase-associated protein 2 (Skp2) can inhibit autophagy by reducing the expression of lncRNA HOTAIRM1 and the inactivation of GSK3β, and then inhibits the ubiquitination and degradation of PML-RARα, thus inhibiting the transcriptional activation of JunB through the PU.1/PML-RARα transcriptional complex, and ultimately prevents cell differentiation and promotes the progress of APL. When NB4 cells were treated with ATRA and GSK3β inhibitors, the expression of Skp2 was down-regulated, while the expression of JunB was significantly induced by accelerating the degradation of PML-RARα, which contributed to the eradication of APL(Dan et al., 2022). JunB was identified as the target gene of miR-149^*, an oncogenic miRNA, in T-cell acute lymphoblastic leukemia, suggesting that JunB may be a tumor suppressor (Fan et al., 2016). Therefore, restoration of JunB in human acute leukemias may improve disease progression.

Passegue et al. found that lack of JunB in mice can lead to myeloproliferative diseases, similar to human CML (Passegue et al., 2001). Subsequently, yang et al. found that the expression of JunB gene was significantly down-regulated in both CML cells and patients. Low expression of JunB was associated with the clinical stage of the patient, that is, in blast crisis it is less than chronic phase which is less than normal. Mechanism studies have shown that the CpG site in the JunB promoter region of CML patients is highly methylated, and 5-aza-2-deoxycytidine demethylation can partially restore the expression level of JunB, indicating that JunB methylation may be a cause leading to CML (Yang et al., 2003). However, Hoshino et al. found that the down-regulation of JunB expression in advanced CML is not achieved through DNA methylation, which was suggested by the fact that JunB methylation was not observed in all CML cell lines studied, and only 3% of CML patients showed JunB methylation (Hoshino et al., 2009). Therefore, the cause of abnormally low level of JunB in CML needs further investigation, and post-translational regulation should be taken into consideration. Liu et al. used JunB as a detection index to evaluate the efficacy of CML patients after receiving imatinib treatment, and found that increased expression of JunB combined with decreased expression of BCR-ABL is a good predictor of clinical prognosis in patients with CML after receiving imatinib treatment (Liu et al., 2006). However, more clinical studies and long-term follow-up are needed, and the intrinsic mechanisms of JunB in leukemia needs to be revealed.

Female breast cancer (BC) has now surpassed lung cancer, becoming the leading cause of global cancer incidence in 2020. It is estimated that there are 2.3 million new cases, accounting for 11.7% of all cancer cases (Sung et al., 2021). Organ metastasis is one of the leading causes of high mortality in BC. Recent studies shows that bone, lung, liver and brain are generally regarded as the main targets for BC metastasis (Liang et al., 2020). In 2013, Kharman-Biz et al. revealed the expression of JunB was negatively correlated with tumor stage and lymph node status, speculating that increased JunB may be related to a less aggressive phenotype and indicating a tumor suppressive role of JunB in BC (Kharman-Biz et al., 2013). Intriguingly, the expression of JunB is significantly upregulated in patients with inflammatory breast cancer compared to those with non-inflammatory breast cancer (Bieche et al., 2004), suggesting that JunB may play a regulatory role in the underlying inflammatory processes in. The TME is composed of all the non-cancerous cells in the tumor, including fibroblasts, endothelial cells, neurons, adipocytes, adaptive, and innate immune cells, and the non-cellular components, including cytokines, chemokines, growth factors, extracellular vesicles and extracellular matrix (ECM)(Xiao and Yu, 2021). Communications between non-cancer cells and cancer cells in TME are critical regulators of tumor initiation, growth and metastasis (Zhao et al., 2021). Recently, Schulz et al. found that JunB was highly expressed in stromal cells of human breast cancer, such as endothelial cells, cancer associated fibroblasts (CAFs) and immune cells. Stromal loss of JunB in mice led to increased tumor metastasis to lung. In addition, an increase in the density of pulmonary vessels was observed in JunB knockout mice. These results remind us of the key regulatory functions of JunB in neovascularization, angiogenesis and vascular system. It is known that an aberrant remodeled tumor vessel and frequently leakier vasculature enhance the intravasation and extravasation of disseminated tumor cells(Schulz et al., 2019). Nevertheless, the tumor blood and lymphatic vascular density and integrity were not influenced upon JunB deficiency. Of note, lack of JunB promoted the recruitment of myeloid cells at the early metastatic stage. Further experiments concluded that a significant increase of neutrophils in circulation is the main reason for distant metastasis induced by JunB deficiency. BV8 and MMP9, two proteins that promote angiogenesis and tissue remodeling, were upregulated in these neutrophils in a JunB-dependent manner, suggesting that neutrophils with JunB loss facilitates angiogenesis and vascular remodeling in the pre-metastatic lungs (Wutschka et al., 2021). It can be concluded that JunB performs a tumor suppressive role in breast cancer through regulating the performance of neutrophils in the TME. However, specific knockout of JunB in CAFs, a major cell group in the TME, had no effect on distant metastasis of breast cancer cells, indicating that an altered secretome of JunB-KO CAFs is not the metastatic driver although JunB regulates the proliferation, differentiation and senescence of fibroblasts (Papaioannou et al., 2018; Maity et al., 2021; Wutschka et al., 2021). In addition, the regulatory role of JunB in T cells was also excluded since T cell infiltration is not obvious in the early metastatic lungs (Wutschka et al., 2021), although JunB is recognized as a fate determiner of T cells.

According to GLOBOCAN in 2020, prostate cancer (PCa) is the second most common cancer among men worldwide, and its incidence may still rise (Sung et al., 2021). Transient amplifying cells (TACs) are a group of basal cell populations in the prostate, and are considered as the origin of PCa (Schalken and van Leenders, 2003). In recent years, JunB was found to decrease during PCa development, which promoted proliferation, invasion and senescence of PCa cells, as well as remodeled the TME. Konishi et al. reported that JunB expression closely paralleled the levels of p16 expression in both pre-senescent and post-senescent TACs. Further experiments indicated that JunB is an important upstream regulator of p16, which contributes to cell senescence and thus prevents the malignant transformation of TAC (Konishi et al., 2008). Later, one study conducted by Thomsen et al. reconfirmed a suppressive role of JunB in PCa. Mechanically, they found that JunB can prevent invasive PCa cells in Pten-deficient mice, and the absence of JunB leads to increased proliferation and decreased senescence of TACs. In addition, loss of JunB in prostate epithelium of Pten-deficient mice led to the change of surrounding stroma, as suggested by the increase of S100A8, S100A9 and SPP1, proteins related to aggressive PCa, especially in monocytes/macrophages although didn’t influence the number of infiltrating immune cells (Thomsen et al., 2015). JunB may regulate the cross-talk between stromal cells and TACs, thereby repressing PCa. Noteworthily, a recent study by Guan et al. found that miR-95, which was delivered by exosomes from tumor-associated macrophages, promoted proliferation, invasion, and EMT of PCa cell by targeting JunB (Guan et al., 2020). Therefore, JunB possibly inhibits the occurrence of PCa by impacting the expression of key non-cellular constituents in TME. In addition, since JunB is an important determinant of immune cells fate and regulates the secretion of inflammatory cytokines, it is an interesting question whether JunB can promote the anti-tumor effect of immune cells in PCa.

Renal cell carcinoma (RCC) is one of the most fatal diseases of the genitourinary system, among which clear cell RCC (ccRCC) accounts for 75-80% of total cases (Ahluwalia et al., 2021). At the molecular level, the loss of tumor suppressor gene von Hippel-Lindau (VHL) function on chromosome 3p25 led to the occurrence of ccRCC. Kanno and co-workers found that JunB increased in VHL-defective ccRCC samples, and JunB knockdown inhibited invasiveness of VHL-null ccRCC cells by controlling the expression of MMP2, MMP9 and chemokine (C-C motif) ligand-2 (CCL2). In vivo xenograft tumor results demonstrated that inhibition of JunB could repress tumor growth and angiogenesis, suggesting that JunB may be an oncogene in ccRCC (Kanno et al., 2012). Further studies suggested that CCL2, the downstream effector of JunB, promotes ccRCC through promoting tumor angiogenesis and recruiting macrophages. Thus, JunB may regulate the TME in ccRCC, but whether JunB directly control the stromal cells remains to be investigated (Arakaki et al., 2016; Zhang et al., 2021). However, the upstream regulatory factors that promote the abnormal expression of JunB in ccRCC have not been revealed. Given that growth factors and inflammation factors have been shown to stimulate the expression of JunB, it raises the question whether non-cellular constituents within the TME may also influence JunB expression in ccRCC.

Multiple myeloma (MM) is the second most common hematological malignancy, characterized by excessive clonal proliferation of malignant plasma cells in the bone marrow (BM), renal disease, immune deficiency, and osteolytic bone lesions, which brings economic burden to human beings (Fan et al., 2021). Increasing BM angiogenesis accelerates disease progression in MM patients and correlates poor prognosis. Recently, Fan et al. found that JunB was significantly induced in MM cells when co-cultured with bone marrow stromal cells (BMSCs), while other AP-1 members, such as c-Jun, JunD, c-Fos, and c-Maf, were moderately upregulated or undetectable (Fan et al., 2017). Further investigations indicated the indispensable role of JunB in MM, including promoting cell survival, proliferation and drug resistance, as well as activating the transcription of pro-angiogenic factors (AFs), such as VEGF, VEGFB, and IGF1, and eventually leading to angiogenesis of bone marrow in MM models (Fan et al., 2017; Fan et al., 2021). Notably, the abnormal upregulation of JunB was elicited by stroma, particularly IL-6, but not hypoxia, which is MEK/MAPK- and NF-κB-dependent but Ras-independent mediator for the transcription of abovementioned AFs (Fan et al., 2021). Therefore, TME influences the expression of JunB in tumor cells, which plays a vital role in promoting BM angiogenesis during MM development. However, the intrinsic molecular mechanism of JunB upregulation is still unclear, and whether other stimuli, such as stiffness of ECM in the TME, promotes MM growth remains to be investigated. In addition, proper expression of JunB is essential to maintain a pro-angiogenic role of endothelial cells at homeostasis in vivo. In malignancies, such as MM, drug design for JunB will help to develop new strategies to slow down the progress of cancer.

A growing number of studies found that JunB is a potential oncogene in lymphoma, including Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL). HL is most frequently seen in young adults, and is classified into classical HL, an aggressive phenotype, and nodular lymphocyte-predominant HL, an indolent phenotype, according to histomorphology (Shanbhag and Ambinder, 2018). ALCL is a rare aggressive peripheral/mature T-cell lymphoma in children and young adults, and is classified into ALK-positive (ALK+) and ALK-negative (ALK-) ALCL (Leventaki et al., 2020). Aberrant upregulation of c-Jun, JunB and CD30 is a hallmark of tumor cells in HL and ALCL. In 2002, Mathas et al. found that ectopic expression of c-Jun and JunB promoted proliferation of HL cells in vitro. Differently, upregulation of c-Jun is mediated by an autoregulatory pattern while JunB is dependent on NF-κB activation in HRS cells (Mathas et al., 2002). Besides, knockdown of c-Jun or JunB inhibited the growth of classical HL cell lines through augmenting G1 phase arrestation (Mathas et al., 2002). This role of JunB instead of c-Jun was confirmed in ALK-positive ALCL (Zhang et al., 2018), which indicated that c-Jun and JunB had similar roles in HL, but different roles in ALCL. Nevertheless, Watanabe et al. reported that in ALCL and HRS cells, CD30 induced JunB expression by activating ERK1/2-MAPK signals, which is not nuclear NF-κB dependent way. In parallel, JunB could bind to the unmethylated promoter of CD30 through the AP-1 site in ALCL, thereby contributing to high expression of CD30 (Watanabe et al., 2005; Watanabe et al., 2008). ALCLs are frequently associated with chromosomal translocations, leading to abnormal expression of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). Subsequently, they found that E26 transformation-specific-1 (Ets-1) promotes the activity of JunB promoter, which depended on CD30 or NPM-ALK-ERK1/2 MAPK pathway in HL and ALCL(Watanabe et al., 2012). Laimer et al. found that in NPM-ALK-induced mouse lymphoma models, c-Jun and JunB enhanced lymphoma development and tumor metastasis by transcriptionally regulating platelet-derived growth factor receptor B (PDGFRB) expression. Moreover, their evidence showed that therapeutic inhibition of PDGFRB significantly prolonged the survival time of NPM-ALK transgenic mice, and promoted the efficacy of ALK-specific inhibitors in transplanted NPM-ALK tumors (Laimer et al., 2012). In pediatric ALCL, it was reported that miR-939 regulates PDGFRB expression through targeting JunB. Although c-Jun is also important for regulating PDGFRB transcription in ALCL, overexpression of miR-939 does not affect c-Jun expression (Garbin et al., 2021). Therefore, JunB is a crucial transcription factor in HL and ALCL, and it is necessary to explore new drugs targeting JunB to inhibit the progression of these cancers.

In addition to the abovementioned cancers, emerging evidence has unveiled the aberration and oncogenic potential of JunB in diverse malignancies, including hepatocellular carcinoma (Zhang et al., 2021), oral squamous cell carcinoma (OSCC) (Tsunoda et al., 2021), head and neck squamous cell carcinoma (HNSCC)(Hyakusoku et al., 2016), epidermal neoplasia (Jin et al., 2011), ovarian cancer(OC) (Teng and Zheng, 2017) and lung cancer (Wanna-udom et al., 2020). For example, JunB has been identified as an overexpressed member of AP-1 transcription factor in OSCC. Subsequent investigation indicated that the c-Jun/JunB heterodimer promotes IL-8 transcription in human OSCC derived cell lines (Tsunoda et al., 2021), suggesting the oncogenic role of JunB may be attributed to the formation of complexes with other transcription factors, such as c-Jun. In HNSCC, knockout or knockdown of JunB could inhibit tumor cell migration and invasion in vitro, and repress distant lung metastasis in vivo, suggesting JunB may be an oncogene in HNSCC progression, but more studies are necessary to be performed to support this point (Hyakusoku et al., 2016). Teng et al. found that JunB was a target of miR-1908, and high expression of JunB correlated with poor prognosis of OC patients (Teng and Zheng, 2017). However, the underlying mechanisms of JunB in genesis of OC need to be clarified. Recently, it was found that both JunB and c-Jun were upregulated in TGF-β1 treated lung cancer cell lines, A549 and LC2/ad. Further studies indicated that METTL3 m6A methyltransferase regulates JunB mRNA and c-Jun protein expression at 3’-UTR in TGF-β1 induced EMT in lung cancer, respectively (Wanna-udom et al., 2020; Suphakhong et al., 2022). This intriguing result was attributed to the fact that different RNA readers bind c-Jun and JunB, YTHDF3 binds c-Jun, and IGF2BP1 binds JunB (Suphakhong et al., 2022). Considering the essential role of JunB in Th2 cells-mediated cytokines production during allergic asthma, further exploration is warranted to determine whether it also exerts regulatory functions within the microenvironment of lung cancer.