Immune checkpoint activation is a critical mechanism by which tumor cells evade clearance by immune cells. In the TME, where tumor cells are located, the surface antigens of tumor cells cannot be presented to T cells, resulting in tumor cells evading immune killing. Programmed death receptor-1 (PD-1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) are the most common immune checkpoint receptors expressed on the surface of T lymphocytes (60). YY1 has been shown to positively regulate immune checkpoint receptors such as PD1 and CTLA-4 (61), and YY1 was upregulated in PD1-positive T cells infiltrating lymphocytes in melanoma tumors and directly regulated the expression of PD1 and LAG3 by binding to the promoter region (62, 63). PD-1 is a critical receptor expressed on activated T cells that inhibits T cell-mediated immune responses upon binding to its ligand programmed cell death ligand 1 (PD-L1) (64). YY1 can increase PD-L1 expression through various signaling pathways. As a negative regulator of p53, YY1 inhibits the expression of miR-34a downstream of p53, while downregulation of miR-34a expression leads to an increase of PD-L1 expression by binding to the PD-L1 3’UTR (65). YY1 has also been shown to promote PD-L1 expression by downregulating PTEN via p53 and activating the PI3K/Akt/mTOR pathway (66). YY1 has been reported to be associated with T cell apoptosis. FGL1 promotes the secretion of interleukin-2 by T cells and induces their apoptosis. Indeed, YY1 is the upstream molecule of FGL1, which was found to be transcriptionally regulated by YY1 (67). These results suggest that YY1 may hinder T-cell-mediated tumor immunotherapy by interfering PD-1/PD-L1 checkpoint.

As the tumor progresses, the TIME is constantly changing, and the speed of tumor development depends on the proportion and characteristics of T cells within the TIME. As early as ten years ago, evidence in the field of tumor immunity suggested that the TME limits the accumulation of T cells among tumor cells. Regulatory T (Treg) cells are essential for maintaining immune homeostasis (60, 68). Hwang et al. showed that the expression of YY1 in Treg cells was lower than that in Tconv cells, and the overexpression of YY1 led to a significant decrease in the expression of Foxp3, making the suppressive function of Treg cells ineffective (69). As one of the most concerned phenotypes in the CD4 T cell family, Treg cells are an immunosuppressive subtype in nature, but with a dual personality as an angel side, Treg cells can regulate the immune system, inhibit the pathological immune response caused by the overactivation of autoreactive T cells, and control inflammation. It plays a key role in maintaining autoimmune tolerance and immune homeostasis. However, in the tumor microenvironment, it shows a devil side. It inhibits the proliferation, metabolism and killing function of CD8 T cells by secreting inhibitory factors such as IL-10, TGF-β and affecting the maturation of dendritic cells (DC). It induces the immune escape of tumor cells by inhibiting the anti-tumor immune response, thus promoting the growth and proliferation of tumors (70). Foxp3 is the critical transcription factor for Treg cell function and differentiation (71). YY1 physically interacts with Foxp3 to directly switch on Foxp3 target genes and interfere with Foxp3-dependent target gene expression. Thus, YY1 inhibits the Treg cell’s differentiation and function by blocking Foxp3 (69, 72). YY1 is a polycomb group (PcG) protein and an original member of the local group of sequence-specific DNA-binding PcG proteins in mammals (73). PcG proteins silence target genes through histone modification, especially methylation modification (74). By contrast, YY1 promotes early T cell survival through its PcG function. In the thymus, T cell development begins when double negative (DN) progenitor T cells lacking CD4 and CD8 expression become CD4⁺CD8⁺ double positive pre-T cells (DP) and then differentiate into mature single CD4⁺ or CD8⁺ positive cells, DN cells have four stages (75–77). Ana et al. demonstrated that YY1 promotes DN1 to DN2 T cell transition and early T cell survival independent of PcG/REPO domain function (78). Overall, YY1 is crucial for T-cell differentiation, function, and development, but YY1 has opposite effects on T-cell development and function ( Figure 2 ).

B lymphocytes are derived from bone marrow hematopoietic stem cells through a series of differentiation stages. Activated B cells produce many cytokines involved in immune regulation, the inflammatory response and hematopoiesis (79). YY1 plays an important role in Ig rearrangement and B-cell development. Studies have shown that conditional knockdown of YY1 prevented the transition of pro-B cells to cells in the pre-B-cells and early developmental stages of B cells (58). Subsequent proof found that YY1 regulates the germinal center B-cells (GC B cells) transcriptional program (59). In specific deletion of YY1 in GC B cells, B-cell numbers in both unimmunized and immunized conditions are severely reduced. In addition, YY1 also affects the immunoglobulin class switch recombination (CSR) process in splenic B cells. These studies strongly suggest that YY1 is essential for B cell differentiation in all stages and is required for the survival and proliferation of B cells ( Figure 2 ), B-NHL is a heterogeneous lymphoma derived from a B-cell mutation (80). Most intravascular lymphomas are large B-cell lymphomas, it is an aggressive lymphoma with a poor prognosis. The molecular characteristics are similar to germinal center or post-germinal center B cells. such as diffuse large B-cell lymphoma (DLBCL), which is the most common subtype. Ramkumar et al. found that the Smurf2-YY1-c-Myc axis has become an important regulatory mechanism in suppression of B-cell proliferation and consequently lymphomagenesis (81). The anti-tumor effects of B cells depend mainly on the secretion of anti-tumor-associated antigen (TAA) antibodies and the provision of co-stimulatory signals to TAA-specific CD4+T cells to activate T cells. Kruppel-like factor 4 (KLF4) is a member of the zinc finger-containing KLF transcription factor family involved in regulating apoptosis, proliferation, and differentiation of B-cells and B-cell malignancies (82). Martinez et al. identified two YY1-binding sites in the KLF4 promoter region, and overexpressing YY1 resulted in significant promotion of KLF4 (83). However, whether the regulatory role of YY1 in lymphoma is suitable for the regulation of tumor by B cells in the tumor microenvironment needs to be further confirmed in future studies. the direct regulation of YY1 on tumor immune microenvironment in various tumors are shown in Table 3 .

The TME has appreciable numbers of immune cells, including adaptive immune responses, such as T cells and B cells, and innate immune cells, such as macrophages and neutrophils (90, 91). Tumor-associated macrophages (TAMs) infiltrate tumor tissue and play an essential role in the TME (92). Joo et al. reported that YY1 and STAT1 were upregulated in macrophages stimulated by oxidized LDL and subsequently were translocated into the nucleus to upregulated miR-29a, thereby reducing proinflammatory cytokine secretion and dampening inflammatory responses in macrophages. Cyclooxygenase 2 (COX-2) has been reported to be involved in inflammatory environments and lung cancer pathogenesis, and lipopolysaccharide treatment induced YY1 binding to the homologous site of endogenous COX-2 promoter YY1 and enhances its transcriptional activity in macrophages. Mechanically, YY1 was reported to interact with p300 and HDAC1/2 to affect the acetylation status of YY1. However, lipopolysaccharide treatment disrupted this interaction and binding to the COX-2 promoter. Indicated that it may be a competitive relationship between YY1 and COX-2 promoter, p300 and HDAC1/2 after lipopolysaccharide treatment (88). In addition, Xu et al. indicates that miR-301a/YY1/CXCR4 signaling pathway plays an important role in macrophage migration and phagocytosis (87). Hence, these results strongly suggest that YY1 is critically important for the tumor immune microenvironment.

Since glucose is the primary energy source of organisms used in aerobic and anaerobic respiration (97, 98), which is maintains a balance between catabolic glycolysis/oxidative phosphorylation (OXPHOS) and anabolic gluconeogenesis/glycogen production (99). Abnormal glucose metabolism is integral to tumor metabolic reprogramming in the TME (100). YY1 is closely related to the glycolysis process. The glucose transporter mediated by the glucose transporter family (GLUT) is a pacemaker of aerobic glycolysis and, thus, is essential for tumor cell metabolism. YY1 may indirectly participate in reprogramming glucose metabolism in tumor cells by promoting the stability of HIF-1α under hypoxic conditions to enhance GLUT1 and GLUT3 expression (101). Wang et al. also reported that YY1 activates GLUT3 transcription by directly binding to its promoter while enhancing aerobic glycolysis in colon carcinoma cells (102). In NSCLC cells, circ_0000517/miR-330-5p/YY1 axis promotes the proliferation, glycolysis, and glutamine catabolism by regulating the expression of glycolysis and glutamine catabolism-related genes HK2, LDHA, ASCT2 and GLS1 (103). LDHA is a glycolytic enzyme that converts glucose-derived pyruvate into lactic acid. YY1 directly bound to the promoter LDHA, and overexpression of LDHA reverses the inhibitory effect of sh-YY1 on aerobic glycolysis and proliferation of neuroblastoma cells, indicating that YY1 induces aerobic glycolysis and proliferation (104). Glycolysis-related genes are critical to the glycolysis process. In neuroblastoma (NB), researchers searched public neuroblastoma datasets to identify transcriptional regulators and their glycolysis-related genes. They found that the zinc finger domain of YY1 binds a 21 amino acid peptide encoded by an open reading frame upstream of Myeloid zinc transcription factor 1 (MZF1), called MZF1-upep. MZF1 has been found to exert independent prognostic and promotes the aerobic glycolysis and tumor progression. Notably, the combination of these leads to decreased transcriptional activity of YY1 and inhibited transcription of MZF1 and downstream glycolytic genes HK2 and PGK1, therefore inhibiting aerobic glycolysis and NB progression (105). Hepatitis B virus (HBV) pre-S2 mutant induces HCC by inducing endoplasmic reticulum stress and activating the mTOR signaling pathway. Research has found that pre-S2 mutants initiate the glycolytic via activate mTOR signal pathway and activate SLC2A1 in YY1-dependent transcription, contributing to increased aerobic glycolysis, glucose uptake, lactic acid production and release in advanced tumorigenesis of HCC (106). In general, the above studies confirmed that YY1 alters the hypoxic microenvironment of tumor cells by regulating the whole process of glycolysis through different molecular mechanisms in various tumors, thus promoting tumorigenesis.

Since Otto Warburg discovered the characteristic of high-level glycolysis in tumor cell metabolism programming, which not only upregulates the adaptive potential of tumor cells to fluctuating oxygen tension but also produces glycolytic intermediates and increases the pentose phosphate pathway (PPP) (107–109), the primary significance of the PPP can generate nicotinamide adenine dinucleotide phosphate (NADPH) and a variety of monosaccharides. NADPH is the only enzyme specifically used to produce reactive oxygen species (ROS) and is essential for cellular antioxidant defense (110, 111). A recent study by Wu et al. identified that YY1 directly binds to the promoter of G6PD and promotes its transcription activity and expression, therefore, stimulating the PPP and protecting tumor cell from oxidative stress and inducing tumor progression (112). In conclusion, research on the molecular mechanisms of the G6PD-mediated PPP is closely related to YY1-induced tumor cell proliferation and tumorigenesis.

One of the typical features of metabolic changes in cancer cells is high levels of oxidative stress, and higher cellular oxidative stress levels favor the activation of glycolysis and promote tumorigenesis by affecting the signal transduction system, depriving them of normal contact inhibition, and promoting invasion and metastasis (113). The functions of these are complementary to each other. Tseng et al. found that p53 accumulation was reduced by MCT-1 overexpression. However, the levels of manganese-dependent superoxide dismutase (MnSOD) were upregulated through the YY1-EGFR signaling pathway, protecting cells from oxidative damage. On the other hand, limiting ROS production and inhibiting YY1 in lung cancer cells prevented MCT-1-induced cell invasiveness and the EGFR-MnSOD signaling pathway (114). However, ROS and YY1 do not have a definite positive association. According to research, low levels of ROS promoted the production of YY1, while high levels of ROS clearly inhibited it. YY1 was recruited to the antioxidant-responsive element binding site when its expression was stimulated, working in concert with other coregulators and then boosted NRF2-mediated ARE transcription, thereby shielding cells from damage by amplifying the antioxidant response (115). Overall, the available data indicate that YY1 can significantly activate cell glycolysis and ROS metabolism and play a critical role in remodeling the TME ( Figure 3 ).

It has been widely observed that lipid metabolic reprogramming during cancer development confers cancer cells the ability to survive through enhanced lipid synthesis, storage, and catabolism, even under nutrient-limiting conditions. Abnormal lipid metabolism has always been observed in various tumors, and chronic liver disease and nonalcoholic fatty liver disease (NAFLD) are closely related to lipid homeostasis disorder. Accumulating evidence suggests that the hallmark feature of NAFLD is an increase in intrahepatic TG content (116). To investigate the crosstalk between lipid metabolism and YY1 in liver cancer cells, the authors found that several key transcription factors of lipid metabolism and their coactivators were significantly reduced in YY1-knockout HCC cells, such as PPARA/RXRA complex member CHREBP, SREBF2 and FXR and HNF family member HNF4A, FOXA1 and FOXA2 (117–119). Moreover, silencing YY1 suppresses the expression of crucial transcription factors markedly reduced their cooperation at various regulatory levels and various regulatory regions, which are involved in hepatic lipid metabolism regulated by these proteins. Especially the expression of SCD and ELOVL6, which encode key enzymes for adipogenesis, is regulated cooperatively by YY1 and PPARA/RXRA complexes on their promotors (120). In normal cells, cellular fatty acid concentration balance is controlled by the normal synthesis and breakdown of fatty acids. But tumor cells modify lipid metabolism by speeding up fatty acid synthesis while blocking fatty acid breakdown, leading to intracellular lipid buildup, in order to meet the demands of their rapid multiplication and growth. Li et al. demonstrated that YY1 was crucial for alterations in lipid metabolism in HCC cells because it suppresses the expression of the PGC-1β, which is a transcriptional activator of MCAD and LCAD that boosts both enzymes’ expression. The MCAD and LCAD are key enzymes required for FAO and crucial for fostering carcinogenesis (121). Therefore, YY1 upregulation prevented fatty acid β-oxidation, which increased triglyceride levels and lipid buildup in HCC cells and demonstrated the promising potential to accelerate the growth of tumors. Wu et al. also demonstrated that miR-122 could promote lipid droplet formation and triacylglycerol (TG) accumulation in vitro by reducing the stability of YY1 mRNA and upregulating FXR-SHP signaling. Suggesting that YY1 plays an essential role in regulating the accumulation of hepatic lipids, especially hepatic triglycerides (TGs) in the TME (122) ( Figure 4 ).

Glutamine is an essential amino acid to maintain normal cell biological function, including biosynthesis, cell signaling, and preventing antioxidant damage (100). Of note, glutamine metabolism can provide the energy and biomacromolecules required by tumor cells for rapid growth and proliferation, helping them maintain intracellular redox homeostasis and intracellular signaling (123), and their anabolic/catabolic actions are dysregulated in cancer. Following glucose and fatty acid metabolism, oncogene-mediated abnormal glutamine metabolism in tumor cells has emerged as a new energy source (124). The researchers analyzed the effect of the YY1 on biological processes using the DAVID method, and these results suggested that the promotion of glutamine metabolism by YY1 may promote the progression of ESCC by affecting cancer pathways. Furthermore, the expression of key rate-limiting enzymes ASCT2, GLS and GLUT1 showed an upward trend and led to glutamine uptake and production were significantly increased. Briefly, these data support a model that YY1 promotes glutamine metabolism and regulates the development of ESCC (125). We also noted that YY1 promotes the expression of vital rate-limiting enzymes HK2, LHDA, PCNA, ASCT2 and GLS in A549 cells. Accordingly, YY1 obviously promoted glucose-to-glutamate conversion (103). In summary, these studies illustrated the role of YY1 in glutamine metabolism in the tumor, and the role of YY1 and its molecular mechanism on tumor metabolism is shown in Table 4 .