Macrophages, also known as tumor-associated macrophages (TAMs), are one of the most common immune cells in the GB tumor microenvironment. Macrophages have been demonstrated to have both pro- and anti-tumor effects in cancer, depending on their polarization state and the tumor microenvironment (Liu et al., 2017). TAMs are drawn to the cancer site by chemokines like C-C motif chemokine ligand 2 (CCL2), and aid tumor development and invasion by secreting cytokines and growth factors including interleukin-6 (IL-6), TGF-β, and VEGF. TAMs also promote tumor growth by inhibiting anti-tumor immune responses and increasing angiogenesis. TAMs with M2-like characteristics produce markers such as Cluster of Differentiation 206 (CD206) and arginase 1 (ARG1) (Lamszus et al., 2003).

The colony-stimulating factor-1 receptor (CSF-1R) is a tyrosine kinase receptor expressed on macrophages that controls GB-associated macrophage survival, proliferation, differentiation, and polarization. CSF-1R interacts to its ligands (IL-34 and CSF-1), resulting in activation of PI3K, ERK, NFκB and Src mediated macrophage survival and proliferation pathways. Targeting CSF-1R can reduce GB-associated macrophages in the tumor microenvironment and promote GB-associated macrophage repolarization, limiting tumor development, avoiding the recurrence of glioblastoma and promoting cytotoxic T-cell activation (Vegliante et al., 2022).

Several approaches have been proposed to target TAMs in GB, including the use of small molecule inhibitors, monoclonal antibodies, and cell-based therapies. Targeting CCL2 or its receptor CCR2 has been proven in experimental GB models to reduce TAM infiltration and enhance GB cell mortality. The use of chimeric antigen receptor T-cells (CAR-T) that target TAM-specific markers such as CD163 is also being investigated as a viable treatment for GB (Lamszus et al., 2003). TAMs in GB are known to promote angiogenesis as well as tumor growth and invasion. TAMs produce pro-angiogenic factors such as VEGF, which promote blood vessel growth and proliferation in the cancer microenvironment (Vegliante et al., 2022). This procedure is crucial for the tumor development and progression of GB by catering to blood flow requirements for absorbing nutrients and oxygen. The use of chimeric antigen receptor CAR-T cells that target TAM-specific markers such as CD163 is being investigated as a potential therapy for GB (Chen et al., 2017).

According to recent studies, GB has at least two distinct macrophage populations: one that promotes tumor development and another that suppresses tumor growth (Achkova and Maher, 2016). Understanding the diversity of macrophages in the GB microenvironment may lead to the development of targeted therapies.

Microglia are brain immune cells that have been found to have an important role in the microenvironment of GB tumors. Microglia, in particular, are among the most abundant immune cells in the GB environment and are known as tumor-associated microglia. Tumor-associated microglia are drawn to the cancer site by chemokines such as CCL2, and help the tumor to expand and invade by secreting cytokines and growth factors such as IL-6, TGF-β, and VEGF. Tumor-associated microglia in GB are pro-tumor M2-like, as evidenced by the overexpression of markers such as CD206 and ARG1. These M2-like tumor-associated microglia have been demonstrated to assist tumor growth and invasion by inhibiting anti-tumor immune responses and increasing angiogenesis (Kioi et al., 2010; Zhou et al., 2015; Achkova and Maher, 2016).

Furthermore, tumor-associated microglia play an important role in GB treatment resistance, including radiation and chemotherapy. Tumor-associated microglia, in particular, can protect cancer cells from radiation-induced apoptosis by secreting cytokines like IL-6 and TNF-β, as well as increasing chemotherapy tolerance by upregulating drug efflux pumps (Philipsen et al., 2023).

Targeting microglia in GB has been proposed using small chemical inhibitors, monoclonal antibodies, and cell-based therapies. Targeting CCL2 or its receptor CCR2 in preclinical GB models, for example, has been shown to reduce TAM infiltration and boost survival (Mantovani et al., 2004; Wang et al., 2013).

T cells are essential adaptive immune response mediators and play critical roles in anti-tumor immunity. T lymphocytes are present in the tumor microenvironment in GB. However, their activities are frequently compromised by a variety of mechanisms (Li et al., 2011) such as tumor-induced T cell fatigue, immunological checkpoint activation, and regulatory T cell (Treg) invasion. (Fecci et al., 2006). Tumor cells additionally release immunosuppressive cytokines such as transforming growth factor-beta (TGF-β), which inhibits T cell activity (Hussain et al., 2006). Depending on the subtype and functional state of the T cells, as well as the cytokine milieu inside the tumor microenvironment, infiltrating T cells can have both pro-tumorigenic and anti-tumorigenic effects (Wainwright et al., 2012).

Regulatory T cells (Tregs) Tregs, for example, have been demonstrated to promote glioblastoma development by inhibiting the anti-tumor immune response and establishing an immunosuppressive milieu (Berghoff et al., 2017). Effector T cells, on the other hand, have the ability to recognize and eliminate tumor cells but are frequently functionally impaired within the glioblastoma microenvironment due to factors such as the upregulation of immune checkpoint molecules and the accumulation of immunosuppressive cells (Alban, 2018).

B cells are immune cells that generate antibodies and play an important part in the adaptive immune response. In the GB microenvironment, B cells can induce immune suppression and angiogenesis. They can generate cytokines including interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β), which suppress the activity of immune cells like T-cells and NK cells while promoting GB development and invasion (Garg et al., 2017; Jiao et al., 2017). Furthermore, B cells can secrete pro-angiogenic factors such as VEGF, CXC chemokine ligand 12 (CXCL12), and CXC chemokine ligand 13 (CXCL13), which stimulate the formation of new blood vessels, provide nutrients and oxygen to the tumor, and promote GB growth and invasion (Shonka et al., 2013).

B cells also play a role in GB therapeutic response by influencing responsiveness to immune checkpoint inhibitors (ICIs). B lymphocytes can express immunological checkpoints including programmed death-ligand 1 (PD-L1), which interacts with the T cell immune checkpoint programmed cell death protein 1 (PD-1) to cause T cell depletion and immune evasion by GB cells (Pellegatta et al., 2015). Several approaches, including the use of monoclonal antibodies targeting B cells and B cell-derived cytokines, as well as B cell function modulation have been proposed to target B cells in the GB microenvironment. Anti-CD20 monoclonal antibodies, such as rituximab, can reduce B cells and increase survival in GB patients. In addition, inhibitors of B cell-derived cytokines such as IL-10 and TGF-β may be a potential strategy for GB treatment (Cai et al., 2015).

B cells play a role in immune escape and have a direct impact on GB development and progression. B cells isolated from GB patient samples have been shown to promote tumor cell proliferation and migration through the secretion of growth factors such as insulin-like growth factor-1 (IGF-1) and hepatocyte growth factor (HGF). They can also influence the immunological milieu of GB by secreting chemokines such as CXCL13, which is produced mostly by B cells in GB patient samples and is related to enhanced T cell infiltration and improved patient survival (Khan et al., 2020).

Anti-CD20 antibodies like as rituximab have been studied in clinical trials for the reduction of B cells in GB. Combination of Anti-CD20 antibodies with traditional chemotherapy medicines such as temozolomide has increased progression-free survival. Rituximab has also been demonstrated to diminish B cell infiltration in the GB microenvironment and increase immunotherapy effectiveness (Wintterle et al., 2003).

NK cells are innate immune cells that help the body defend against viruses and tumors. NK cells are present in the tumor microenvironment in GB but are frequently functionally compromised (Vivier et al., 2008). NK cells have been demonstrated in studies to infiltrate glioblastomas and may contribute to tumor management via a variety of methods, including the direct killing of tumor cells and activation of other immune cells (Yang et al., 2010). However, NK cells, like other immune cells, can be suppressed within the glioblastoma microenvironment by factors such as immune checkpoint molecule upregulation and immunosuppressive cell accumulation (Hasmim et al., 2015). Tumor cells can cause NK cell dysfunction through a variety of methods, including activating ligand downregulation and inhibitory ligand overexpression (Fujita et al., 2011). Immunosuppressive substances in the tumor microenvironment, such as TGF-β and interleukin-10 (IL-10) (Ho and Ho, 2021), can also limit NK cell activity.

Dendritic cells (DCs) are important components of the immune response and have been linked to glioblastoma (GB) tumor microenvironment. Recent research has shown that DCs can interact with other immune cells in the GB microenvironment, boosting the growth of regulatory T cells (Tregs) through TGF-mediated signaling (Carmeliet and Jain, 2000). DCs release VEGF-A, which promotes tumor development and angiogenesis in GB (Plate et al., 1992b). The presence of DCs in the GB microenvironment implies requires a better understanding into their interactions with other immune cells, that may lead to better treatment methods. Boosting anti-tumor immunity of DCs while suppressing their pro-tumor actions can be an effective strategy for GB therapy.

MDSCs, a diverse population of immature myeloid cells that limit the function of immune effector cells. Several studies have shown that MDSCs promote tumor growth and invasion via a variety of mechanisms, including cytokine and growth factor secretion, immune effector cell suppression, and angiogenesis stimulation. MDSCs secrete IL-6 by activating the signal transducer and activator of transcription 3 (STAT3) signaling pathway, promoting tumor growth and invasion. MDSCs also inhibit NK cell activity by upregulating PD-L1 expression (Eichler et al., 2011).

Depleting MDSCs in the tumor microenvironment can increase the activity of immune effector cells while decreasing tumor development and invasion. In a mouse model of GB, all-trans retinoic acid (ATRA)-mediated MDSC reduction enhanced T cell infiltration and decreased tumor development (Sun et al., 2021). Similarly, targeting S100 Calcium Binding Protein A9 (S100A9), which is expressed by MDSCs, inhibited tumor development and invasion in a mouse model of GB (Hynes, 2002).

Endothelial cells present in the tumor microenvironment play an important role in supporting glioblastoma development and invasion (Reardon et al., 2017). Endothelial cells are important for angiogenesis, which is the development of new blood vessels from pre-existing ones and is a characteristic of glioblastoma growth. These cells have high quantities of pro-angiogenic factors including VEGF, which promote blood vessel creation as well as glioblastoma cell survival and invasion (Silva et al., 2008). Endothelial cells can also influence the immune response by secreting immunosuppressive factors like TGF-β and expressing immunological checkpoint molecules like PD-L1 that decrease T cell activation and proliferation. Endothelial cells can also modify the extracellular matrix (ECM) of glioblastoma tumors, allowing glioblastoma cells to migrate and invade (Tawi et al., 2021).

Several strategies have been developed to target endothelial cells in glioblastoma therapy. One such strategy is to use monoclonal antibodies or small molecule inhibitors to limit VEGF signaling and hence reduce angiogenesis. Another strategy is to target endothelial cell survival and migratory pathways such as PI3K/Akt and mTOR (Charles et al., 2012). However, these approaches have limitations and can interfere with normal endothelial cell functions, resulting in negative outcomes (Liang et al., 2014). Immunotherapy is another intriguing strategy that targets the immune regulatory activities of endothelial cells. Anti-PD-L1 antibodies have shown potential therapeutic effects in glioblastoma tumors by increasing T-cell infiltration and activation. In preclinical investigations, combining anti-PD-L1 treatment with other immune checkpoint inhibitors, such as anti-cytotoxic T-lymphocyte–associated antigen 4 (anti-CTLA-4), yielded encouraging outcomes (Cekanaviciute et al., 2014). However, more research is needed to develop safe and effective therapeutic strategies for glioblastoma tumors that target endothelial cells.

Astrocytes, the most common glial cells in the central nervous system, have been revealed to play an important role in glioblastoma tumor microenvironment. Glioblastoma tumor-induced astrocyte activation can increase tumor growth. Activated astrocytes release cytokines and growth factors that promote glioblastoma cell proliferation and invasion. Astrocyte activation has also been linked to a poor prognosis in glioblastoma patients (Olea-Flores et al., 2020). Astrocytes can produce immunomodulatory substances such transforming growth factor- (TGF-β) and interleukin-10 (IL-10), which dampen the immune response to glioblastoma cells. Furthermore, astrocytes can inhibit the activity of immune cells involved in anti-tumor immunity, such as T-cells and NK-cells (Farin et al., 2006).

Astrocytes, in addition to immunological regulation, can enhance angiogenesis in the glioblastoma microenvironment. Astrocytes also have the ability to produce vascular endothelial growth factor (VEGF), a critical regulator of angiogenesis, and express integrins as well as extracellular matrix proteins that aid in the formation and stabilization of blood vessels (Nagy et al., 2010). Astrocytes have also been found to contribute to drug resistance in glioblastoma tumors by secreting factors that protect glioblastoma cells from chemotherapy. Additionally, astrocytes can form a physical barrier between glioblastoma cells and chemotherapy agents, preventing them from reaching the tumor cells. They can also activate signaling pathways that promote drug resistance in glioblastoma cells (Zhao et al., 2008). Understanding the role of astrocytes in glioblastoma tumor microenvironment is essential for the development of effective treatments for this devastating disease.

In recent research, neurons in the GB microenvironment have been identified as a potential contributor to tumor formation. Glutamate and substance P, for example, have been shown to promote GB cell motility and invasion. It has been demonstrated that the synthesis of chemicals like brain-derived neurotrophic factor (BDNF) by neurons can promote cancer growth by boosting angiogenesis (Venkatesh et al., 2017).

Neurons in the GB microenvironment are not passive bystanders; rather, they engage in active interactions with glioblastoma cells. Glioblastoma cells on the other hand promote the formation of synapses between neurons, resulting in enhanced neuronal activity (Venneti et al., 2015). Neurons, have been shown to alter glioblastoma cell behaviour through the synthesis of BDNF and neuregulin-1 (NRG1) (Venkataramani et al., 2019). Recent research has shown that glioblastoma cells can form direct synapses with neurons, allowing impulses to be transmitted between the 2 cell types (Lu et al., 2012).

The interaction of neurons and glioma cells involves complex signaling pathways (Venkatesh et al., 2019). The binding of BDNF to its receptor TrkB on glioblastoma cells, for example, has been shown to promote tumor development and invasion by activating many signaling pathways such as PI3K/AKT, MEK/ERK, and PLC. Similarly, binding of NRG1 to its receptor ErbB3 on glioblastoma cells has been shown to increase cancer cell survival and invasion via the PI3K/AKT and MEK/ERK pathways (Kermani et al., 2005).

The discovery of neurons’ participation in the GB microenvironment has significant implications for GB treatment (Zhang et al., 2008). In preclinical studies, blocking BDNF signaling was shown to reduce GB development and invasion. Inhibiting NRG1 signaling also improves glioblastoma cell susceptibility to radiation treatment (Zhang et al., 2014). Targeting neuronal signaling pathways, could therefore emerge as a novel therapeutic strategy for GB.

Vascular endothelial growth factors (VEGFs) and receptors (VEGFRs) play critical roles in vasculogenesis and angiogenesis (Quail and Joyce, 2017). Endothelial cell proliferation and survival are largely driven by the ERK, neuropilin-1 (NRP1), and PI3K/Akt pathways, which are triggered by a variety of signaling intermediates (Takahashi et al., 2001). Endothelial cell migration is regulated by several mechanisms that frequently converge on PI3K stimulation, resulting in the activation of Rho family G proteins. VEGF can also attach to NRP1 on endothelial cells, boosting VEGF binding to VEGFR2 and magnifying its pro-angiogenic effects (Garrido-Urbani et al., 2009). MMPs are upregulated by VEGFA predominantly through Akt-dependent activation of -catenin and nuclear factor kappa B (NFκ-B) and ROS-mediated mechanisms (Van Hinsbergh and Koolwijk, 2008).

Following the discovery of VEGF as a key regulator of pathologic angiogenesis and tumor growth in glioblastoma, VEGF and VEGFR inhibitors have been developed (Gerstner et al., 2009). The first anti-angiogenic medication approved for cancer therapy was bevacizumab, a human monoclonal antibody that precisely recognizes and inhibits VEGF-A (Vredenburgh et al., 2007). However, resistance mechanisms such as the activation of alternative angiogenic pathways and the recruitment of pro-angiogenic immune cells have limited anti-angiogenic therapy’s clinical effectiveness in glioblastoma (Gilbert et al., 2014).

FGFs are a class of growth factors that govern angiogenesis and have been linked to the development of GB. FGFs bind to four tyrosine kinase receptors (FGFR1-4) on the cell surface, activating a variety of signaling pathways such as PI3K, PLC, mitogen-activated protein kinases (MAPK), signal transducers and activators of transcription (STATs), and protein kinase C (PKC). These mechanisms increase cell proliferation, survival, and migration, which are required for tumor angiogenesis (Hadari et al., 2001). FGF expression is elevated in glioblastoma and is associated with tumor grade and patient prognosis. FGFs enhance angiogenesis by boosting endothelial cell proliferation and migration (Udayakumar et al., 2002), triggering the production of pro-angiogenic molecules such as VEGF, and affecting extracellular matrix remodeling during angiogenesis (Takahashi et al., 1992). Because of FGF’s crucial involvement in glioblastoma tumor angiogenesis, treatments targeting FGF signaling pathways, such as FGFR inhibitors and combination therapies targeting FGF and other pro-angiogenic pathways such as VEGF, have been developed (Shah et al., 2008; Koch et al., 2012).

Platelet-derived growth factor (PDGF) family members include PDGF-AA, AB, BB, CC, and DD, which activate intracellular signaling pathways such as Ras-MAPK, PI3K, and PLCg (Vredenburgh et al., 2007) to kick-start the cell cycle, DNA synthesis, mitosis, cell migration, and chemotaxis (Galanis et al., 2018). GB is characterized by elevated PDGF and PDGFR expression. Preclinical investigation in rats and marmosets revealed that PDGF overexpression, particularly PDGFB and PDGFA play an important role in the genesis and progression of GB (Saha and Giri, 2017). Furthermore, it has been demonstrated that low molecular weight PDGF receptor kinase inhibitors effectively reverse the transformed phenotype and inhibit tumor growth in vivo. In GB, PDGF/PDGFR targeting has shown promising therapeutic outcomes (Xu et al., 2015). PDGF genes express differently in glial cells and endothelial cells in GB micro-environment, while PDGFR is preferentially expressed in GB stem cells, encouraging their self-renewal and invasion (Ozawa et al., 2014). Endo-MT and VEGFR-2 down-expression are regulated by the PDGF/NF-B/Snail axis in GB, resulting in resistance to anti-angiogenic treatment. Inhibiting PDGF signaling improves the sensitivity of anti-VEGF/VEGFR therapy in GB, allowing for the creation of more effective treatment regimens (Uhrbom et al., 2004). PDGF-D is a potent growth factor for human GB cells, and HIF1 plays an important role in the constitutive activation of the AKT signaling pathway in GB by regulating the expression of PDGF-D and its receptor, PDGFR. Inhibition of HIF1α disrupts the HIF1α-PDGF-D-PDGFRα feedforward axis, leading to the abolishment of AKT pathway activation and a potentially effective therapeutic approach for GB treatment (Liu et al., 2018).

Hepatocyte growth factor (HGF), also known as scatter factor (SF), is a heparin-binding mesenchyme-derived cytokine that has been linked to glioblastoma multiforme (GB) angiogenic process. HGF/SF has been established in recent investigations to play an important role in GB tumor angiogenesis by boosting endothelial cell proliferation, migration, and survival (Peng et al., 2021).

HGF/SF is a strong mitogen that promotes endothelial cell growth. The binding of HGF/SF to its receptor, c-MET, stimulates multiple downstream signaling pathways that promote cell proliferation, including the PI3K-AKT, RAS-ERK, and JAK-STAT pathways. HGF/SF has been demonstrated to increase endothelial cell proliferation in GB by activating the PI3K-AKT and RAS-ERK pathways (Trusolino and Comoglio, 2002).

The hepatocyte growth factor/scatter factor (HGF/SF) has been linked to the control of angiogenesis through the overexpression of VEGF, a powerful pro-angiogenic factor, and the reduction of thrombospondin 1 (TSP-1), an endogenous regulator of angiogenesis. This dual method of action shows that HGF/SF is important in balancing pro- and anti-angiogenic factors in the tumor microenvironment (Olmez et al., 2018).

Angiopoietins (Angs) are a protein family that binds to the Tie-2 receptor and play an important role in GB angiogenesis. Angiopoietins are classified into four kinds, each with distinct and opposing actions on the vasculature (Knowles et al., 2009). Angiopoietin-1 (Ang-1) promotes endothelial cell survival, proliferation, migration, and tube formation by activating the Tie2 receptor tyrosine kinase and stabilizing blood vessels. It also stimulates the recruitment of pericytes and smooth muscle cells to the vessel wall, which helps to stabilize it. Ang-1 causes new vessel development with angiogenic activities independent of VEGF and stabilizes them via reciprocal interactions between the endothelium and the surrounding extracellular matrix (Suri et al., 1996a; Suri et al., 1996b).

Ang-1 and Ang-2 are key Ang family members that connect to the Tie-2 receptor on endothelial cells. Ang-1 promotes blood vessel stabilization, whereas Ang-2 promotes vascular remodeling by destabilizing blood vessels and inducing sprouting angiogenesis (Daly et al., 2006a). Ang 2 also stimulates downstream signaling pathways that induce angiogenesis, such as AKT and ERK (Ricci-Vitiani et al., 2010). The invasiveness of gliomas is linked to Ang-2 upregulation. Inhibiting Ang-2 expression can reduce glioma invasiveness and avoid an anti-VEGF therapeutic escape mechanism. Dual suppression of the VEGF and angiopoietin-TIE2 signaling pathways is thought to be a potential treatment option for recurrent GB (Kienast et al., 2010). The role of Ang-1 in GB angiogenesis on the other hand is controversial, with some studies showing that it can suppress GB angiogenesis by stabilizing blood vessels and reducing vessel permeability (Huang et al., 2010).

The TGF- family of structurally similar polypeptides regulate several pro-tumorigenic processes, including proliferation, apoptosis, differentiation, epithelial-mesenchymal transition (EMT), and angiogenesis. TGF-β signaling can activate downstream effectors that govern cellular activities such as the canonical Smad pathway, which includes the Wnt, Notch, Hippo, Hedgehog, and JAK-STAT pathways, as well as non-Smad pathways such as PI3K-Akt, MAPK, and Rho GTPases (Akwii et al., 2019).

The key process of epithelial-mesenchymal transition (EMT) promotes the growth of GB. E2 and TGF-β have been found to suppress the expression of the estrogen receptor (ER) and Smad2/3. TGF-β causes Smad2 phosphorylation and subsequent nuclear translocation, which is blocked by E2. Both E2 and TGF- β have been discovered to elicit EMT-related cellular processes such as morphological alterations, actin filament reorganization, and mesenchymal marker expression (N-cadherin and vimentin). Interestingly, co-treatment with E2 and TGF- β has been shown to inhibit EMT activation (Daly et al., 2006b).

TGF- β is linked with a poor prognosis in GB and promotes the production of pro-angiogenic factors such as VEGF, FGF, and PDGF-β (Itoh et al., 2018). TGF-β1 enhances glioma-induced angiogenesis via the JNK pathway in zebrafish embryo/xenograft glioma models (Li and Flavell, 2008). Crosstalk between TGF-β and VEGF/PLGF signaling has been demonstrated to exhibit both pro- and anti-angiogenic actions in human brain-derived microvascular endothelial cells (hCMECs) and glioblastoma-derived endothelial cells (GMECs). TGF-β increases VEGF and PlGF mRNA and protein expression in glioma cells, resulting in pro-angiogenic effects. Exogenous TGF-β, on the other hand, inhibits endothelial characteristics and causes endothelial-mesenchymal transition (EndoMT) in hCMEC and GMEC (Liu et al., 2012).

Matrix metallopeptidases (MMPs) are a class of structurally conserved zinc-dependent endopeptidases generated by tumor cells that play a crucial role in tumor development invasion, metastasis, and angiogenesis in the central nervous system through participating in the breakdown of extracellular matrix macromolecules such as angiogenesis and cytokine activation. MMPs stimulate endothelial cell invasion by destroying the vascular basement membrane and ECM (Hernández-Vega and Camacho-Arroyo, 2021). They also promote pericyte proliferation and activation, as well as their migration to newly formed vasculature, resulting in vascular stabilization (Chamberlain, 2013). MMP-9-mediated VEGF release from the matrix has been shown in multiple transgenic mice models that triggers angiogenic switching in pre-malignant tumors (Krishnan et al., 2015).

Guanylate-binding proteins 5 (GBP5) mediated activation of MMP3 plays an important role in the development and invasion of glioblastoma (GB). GBP5 has been demonstrated to activate the Src/ERK1/2 MAPK pathway in GB cells, resulting in the production of matrix metalloproteinase-3 (MMP3). According to research, MMP3 is overexpressed in gliomas and contributes to the aggressiveness of GB. As a result, the GBP5/Src/ERK1/2/MMP3 axis has been postulated as a possible therapeutic target for GB (Sternlicht and Werb, 2001; Bassiouni et al., 2021).