The MET gene, located on chromosome 7 in humans, is an oncogene comprised of 21 exons and 20 introns. Following translation and subsequent post-translational modifications, MET generates a heterodimeric receptor, c-MET, consisting of an extracellular α-chain and a transmembrane β-chain. Within the tumor microenvironment (TME), the specific ligand hepatocyte growth factor (HGF) is predominantly released by fibroblasts associated with cancer [1]. When HGF interacts with the c-MET receptor, it triggers the formation of homodimers and the autophosphorylation of tyrosine residues. The phosphorylation process at these tyrosine sites creates binding points for multiple signaling effectors such as GRB2, SHC, CRK, PI3K, PLCγ, SRC, SHIP2, and STAT3 [2]. Consequently, this initiates the activation of subsequent signaling routes linked to c-MET, including RAS/MAPK, PI3K/AKT, Wnt/β-catenin, and JAK/STAT [3,4,5]. Cell growth, proliferation, and survival are governed by the HGF/c-MET signaling pathway, which operates through complex downstream signaling sequences. Furthermore, it is crucial for embryo development, organ formation, tissue regeneration, wound healing, and tissue repair [6].

The disruption of the HGF/c-MET signaling pathway, which has been preserved through evolution, leads to a complex array of events within cells that contribute to the development of tumors. Numerous studies have confirmed the critical importance of irregular HGF/c-MET signaling in promoting growth, invasion, metastasis, apoptosis resistance, initiation of epithelial-mesenchymal transition (EMT), and enhancement of angiogenesis [7,8,9,10] (Fig. 1). In particular, the irregular activation of the HGF/c-MET pathway enhances the survival of glioma cells via PI3K signaling [11], augments the spread of squamous cell carcinoma through STAT3 signaling [12], promotes the attachment of lymphoma cells via PI3K signaling [13], boosts the growth of head and neck squamous cell carcinoma (HNSCC) through MAPK signaling [14], and triggers EMT and invasion in prostate cancer through Erk/MAPK signaling [15]. To sum up, the HGF/c-MET signaling pathway is crucial and complex in both normal cell function and cancerous growth.

Fig. 1

HGF/c-MET signaling pathway network: After tumor-associated fibroblasts (CAF) produce and secrete inactive precursor HGF (Pro-HGF), Pro-HGF is converted to active HGF by matriptase on the surface of the cancer cell and binds to its receptor c-MET, resulting in heterodimerization of c-MET monomers. Residues Y1234 and Y1235 present in the catalytic domain undergo autophosphorylation, which in turn phosphorylates the C-terminal tyrosine residues (Y1349, Y1356), and serves as a docking site for downstream bridging molecules. The downstream docking molecules include GAB1, GRB2, SHC, CRK, PI3K, PLCγ1, SHP2, and STAT3, which further activate the downstream pathways of HGF/c-MET, including RAS/MAPK, PI3K/AKT, Wnt/β-Catenin, and JAK/STAT, to drive transcriptome changes and ultimately mediate the phenotypic changes of the cancer cells, including proliferation, migration, invasion, and metastasis. This figure was created using Figdraw

Oncogenic dysregulation and treatment of the HGF/c-MET signaling pathway

c-MET falls under the category of receptor tyrosine kinases (RTKs) and originates from the genetic blueprint of the MET oncogene. The enhanced extracellular portion of c-MET is composed of three distinct structural areas: the N-terminal Sema domain, the extracellular α-chain, and a segment of the transmembrane β-chain, which features four IPT structural domains and a PSI structural domain [16]. c-Met receptors engage with HGF via paracrine, endocrine, or autocrine pathways. The SEMA domain of the transmembrane chain facilitates interaction by binding to HGF, with additional stabilization provided by the PSI domain [9, 17, 18]. The homodimerization of the c-MET monomer results in the autophosphorylation of tyrosine residues within the catalytic domain, notably Y1234 and Y1235 [19]. The activation initiates autophosphorylation at residues Y1349 and Y1356, leading to the formation of docking points for various adaptor molecules (such as GAB1, GRB2, SHC, CRK, PI3K, PLCγ1, SHP2, and STAT3), which facilitate the coordination of subsequent signaling [3, 15, 20]. This mechanism plays a role in activating various downstream pathways, including RAS/MAPK, PI3K/AKT, Wnt/β-catenin, and JAK/STAT, which are crucial for controlling a range of cellular physiological activities such as differentiation, proliferation, epithelial cell movement, angiogenesis, and EMT [21].

The unusual triggering of the HGF/c-MET pathway may lead to tumor development via mechanisms that are both reliant on and independent of ligands. The oncogenic imbalance in the HGF/c-MET signaling pathway is primarily due to genetic changes in autocrine and paracrine pathways. Changes in genetics encompass MET exon 14 skipping mutations (METex14), amplification of MET genes, increased c-MET protein levels, structural domain mutations in MET kinase, and fusion of MET genes [22]. Within this group, mutations in METex14 play a vital role in the coding of MET proteins' parallel membrane structures, which are a key factor in their negative regulation. Alterations resulting from METex14 mutations are marked by the partial removal of the parallel membrane configuration or hindered attachment to the E3 ubiquitin-protein ligase CBL, which impedes MET protein ubiquitination and self-degradation, thereby extending the activation of subsequent signals [23, 24]. Amplification of MET results in a rise in MET mRNA levels, which subsequently elevates MET protein expression and continuously activates the MET signaling pathway. Alterations in the MET kinase domain trigger its phosphorylation, initiating a cancer-causing signaling cascade that leads to the continuous activation of the MET receptor [23, 25, 26]. The translocation of chromosomes may facilitate the fusion of MET genes, resulting in the abnormal production of MET proteins associated with various genes, which impacts their functional areas [23]. Such imbalances foster cancer-causing processes, including cell growth, survival, movement, invasion, and blood vessel formation, thereby encouraging the development of tumors.

During the age of precision-therapeutic medicine, investigating the link between irregularities in the HGF/c-MET signaling pathway and cancer treatment is crucial. Lately, numerous clinical studies have focused on MET irregularities, yielding positive outcomes. For instance, in the case of advanced/metastatic non-small cell lung cancer (NSCLC) with METex14, GEOMETRY mono-1, a multicenter, open-label, multicohort phase 2 trial, demonstrated that capmatinib was highly effective against tumors in patients with advanced or metastatic NSCLC at stages IIIB and IV, particularly those with METex14 or MET amplification, especially in settings without prior treatment [27]. In a group of 69 individuals with MET exon 14 skip mutations undergoing primary or secondary treatment, the total response rate stood at 41%, with a median duration of 5.2 months. Conversely, within the group of 28 patients new to treatment, the general response rate was 68%, with a median response time of 12.6 months [27,28,29]. Following these results, the FDA has approved the use of capmatinib for treating adults with metastatic NSCLC. Although c-MET inhibitors can influence HGF/c-MET signal transduction by inhibiting the abnormal activation of c-MET, some studies have shown that when MET inhibitors are used alone, they cannot significantly improve the prognosis of patients. This may be due to the triggering of various bypass signaling pathways and the diversity of tumors [30,31,32].

Recent research has explored the interplay between MET dysregulation, tumor development, and therapeutic approaches to optimize treatments and enhance their effectiveness. Numerous studies have concentrated on the role of cancer-causing HGF/c-MET pathways in controlling the TME and aiding in the advancement of specific tumors. Furthermore, a possible link might exist between MET dysregulation and immunotherapy, leading to a growing investigation into the rationale behind combining MET TKIs with ICIs.

The HGF/c-MET signaling pathway regulates the TME to promote immune escape

The TME represents a complex cellular environment that is conducive to the growth of tumors and cancer stem cells, and it crucially influences the onset, development, spread, and resistance to cancer therapies. The TME is a complex and multi-layered structure, primarily consisting of cancer cells, cancer-associated fibroblasts (CAFs), cells that suppress the immune system (such as tumor-associated macrophages [TAMs], myeloid-derived suppressor cells [MDSCs], and regulatory T cells), cells that activate the immune system (including natural killer [NK] cells, dendritic cells [DCs], and T cells), and a variety of signaling molecules [33,34,35,36]. TME dynamically influences the progression of tumors and markedly impacts the outcomes of treatments. Previous studies have revealed that alterations in the mechanisms directing tumor development may initiate or interfere with immune responses in the TME, leading to either immune resistance or dysfunction, and eventually resulting in the tumor's avoidance of the immune system. Research indicates that abnormal activation of the HGF/c-MET pathway may influence the growth and activity of immune-suppressing cells in the TME, impacting the multiplication and activation of T and NK cells. This hinders their tumor-eliminating capacity and facilitates tumor immune evasion (Fig. 2). This segment delves into the function of the HGF/c-MET pathway and its subsequent routes in the TME post-activation, encapsulating its impact on various TME cells, as detailed in Table 1.

Fig. 2

Impact of HGF/c-MET Signaling Pathway on Immune-Suppressive Cells and Their Interactions: Immune-suppressive cells primarily include CAFs, TAMs, MDSCs, and Tregs. Firstly, abnormal activation of the HGF/c-MET signaling pathway can activate downstream pathways in M1-type TAMs, such as P13K-Arg1, P13K-HDM1-HIF2, and STAT3, promoting the polarization of M2-type TAMs. M2-type TAMs secrete cytokines like TGF-β, PGE2, and VEGF, which promote tumor progression. Secondly, the HGF/c-MET signaling pathway can activate the STAT3 pathway in MDSCs, leading to MDSC expansion, and promoting Treg proliferation through TGF-β secretion by MDSCs. Tregs can secrete various cytokines (IL-2, IL-10, TGF-β, CTLA-4) to inhibit the function of CTLs and NK cells. Additionally, the HGF/c-MET signaling pathway and FGF19/FGFR4 signaling can activate the ERK1/2-ETV4 downstream pathway in tumor cells, increasing the secretion of CCL2 and promoting the recruitment of MDSCs to the tumor site. CAFs can secrete various cytokines that affect other immune-suppressive cells: they induce M2-type TAM polarization by secreting MCP-1 and Chi3L1, indirectly induce M2 polarization in TAMs by increasing ROS production in M1-type TAMs, participate in the induction and maintenance of Treg cells by secreting VEGF-A, and recruit MDSCs to the tumor site through CCL2 secretion via the STAT3-CCL2 signaling pathway. This figure was created using Figdraw

Table 1 Effects of HGF/c-MET signaling on cells in tumor microenvironmentCAFs and extracellular matrix (ECM) paracrine HGF activate MET signaling

A variety of stromal cells, known as CAFs, exhibit a wide range of origins, phenotypes, and functions [37, 38]. CAFs serve a dual purpose as essential elements in the TME. These elements contribute to the restructuring of the ECM, affect the attraction and functioning of immune cells, and interact with other cells in the TME. Such interactions lead to the formation of an immune-inhibiting TME, allowing cancer cells to escape immune surveillance [39, 40]. As an example, in research focusing on pancreatic ductal adenocarcinoma, Zhang et al. found that CAFs trigger TAM M2 polarization by boosting monocyte ROS production via the release of macrophage colony-stimulating factor [41]. Additionally, research on breast cancer have revealed that CAFs can secrete certain factors to achieve this. For instance, Cohen et al. found that CAFs can secrete glycoprotein chitinase-3-like-1 (Chi3L1), which can enhance the recruitment of TAMs and induce their polarization towards the M2 type [42]. Chi3L1 is a highly conserved secreted protein that contains a conserved chitinase-like domain but lacks chitinolytic enzyme activity [43]. Meanwhile, Ksiazkiewicz et al. found that CAFs can also secrete monocyte chemoattractant protein-1, also known as CCL2, to prompt the polarization of TAMs towards the M2 type [44]. Beyond TAMs, it has been demonstrated that TGF-β, which is secreted by CAFs, markedly reduces and notably hinders NK cell activation and cytotoxicity [45]. A range of compounds emitted by CAFs, such as vascular endothelial growth factor A (VEGF-A), is noted to play a role in the stimulation and sustenance of T regulatory (Treg) cells, either directly or indirectly [46]. Furthermore, it has been documented that CAFs, a primary source of CCL2, trigger the movement of MDSCs to cancerous areas via STAT3-CCL2 signaling transduction [47].

Recent research has shown that CAFs, a significant group of stromal cells in the TME that emit HGF, trigger the HGF/c-MET pathway and its subsequent signals, thereby facilitating tumor movement and advancement. Research centered on colorectal cancer (CRC) revealed that CAFs with Ras-related protein Rab-31 (RAB31) controlled the release of HGF, thus promoting the movement of CRC cells [48]. Blocking the transmission of the HGF/c-MET pathway in CAFs has been demonstrated to impede the movement of CRC cells driven by RAB31 expression, highlighting the role of CAFs in enhancing paracrine HGF release and stimulating the HGF/c-MET pathway, which in turn propels tumor growth [48]. During a live study on gastric cancer (GC), the secretion of HGF by CAFs enhanced the presence of interleukin-6 receptor (IL-6R) in MET non-amplified GC cells via the HGF/c-MET/ERK1/2 signaling pathway [49]. Concurrently, IL-6, originating from CAFS, enhances c-MET expression in GC cells without MET amplification through the IL-6/IL-6R/JAK2/STAT3 pathway [49]. This process activates the HGF/MET pathway, initiating subsequent signaling pathways via STAT3 and encouraging the growth, movement, and infiltration of GC cells. Additionally, Additionally, Wei et al., through their research on ovarian cancer cells, have found that HGF derived from CAFs promotes the growth of ovarian cancer cells by strengthening the c-MET/PI3K/AKT and GRP78 signaling pathways [50]. However, the impact of irregular activation of the HGF/c-MET pathway on CAF activation is still ambiguous and requires further research.

Additionally, CAFs are capable of breaking down the ECM through the release of matrix metalloproteinases (MMPs) and the creation of novel matrix proteins involved in tumor penetration and angiogenesis [51,52,53]. Predominantly, the ECM consists of proteoglycans, glycoproteins, various matrix proteins (such as SPARC/osteonectin, OPN/SPP-1, and THBS/TSP, which are abundant in cysteine residues), and structural proteins (including fibrillin, collagen, and laminin) [54]. The ECM is vital in facilitating tumor transformation, protecting tumors from immune surveillance, and aiding their growth and invasion. Research indicates the ECM plays a role in controlling HGF/c-MET signaling pathways, with components of the ECM known to initiate the HGF/c-MET pathway. For example, extracellular proteases, such as HGFA, matriptase, and MMP-2, can cleave and transform HGFs into their active biological state, thereby facilitating the release of HGF [55]. Furthermore, certain proteases, including MMP-1, ADAM-17, and ADAMTS-1, facilitate the release of EGFR ligands from the cellular membrane. These ligands, when activated by TGF-α or EGF, engage with c-MET, triggering the activation of c-MET signaling independent of the ligand [56].

To summarize, CAFs and ECM within the TME influence the HGF/c-MET signaling pathway through their interactions with immune cells and the secretion of HGF, leading to the formation of an immunosuppressive TME that accelerates tumor growth.

Regulation of TAM polarization

TAMs mainly stem from monocytes originating in the bone marrow and are drawn to cancerous areas via the chemoattractant CCL2, which is produced by tumor cells [57]. Their functions include orchestrating angiogenesis, restructuring the ECM, promoting cancer cell growth, facilitating metastasis, inducing immunosuppression, and contributing to resistance to chemotherapy and checkpoint blockade immunotherapy [58]. Generally, TAMs are categorized into two main types: traditionally activated (M1-like macrophages) and alternatively activated (M2-like macrophages) [59]. During the initial phases of tumor growth, M1-like macrophages, resembling TAM phenotypes in the TME, play a key role in tumor prevention by inducing antibody-driven cytotoxicity, producing ROS, and generating tumor necrosis factor (TNF) [60]. Conversely, macrophages similar to M2 enhance tumor blood vessel formation, immune suppression, cancer cell infiltration, and spread by emitting anti-inflammatory agents such as TGF-β, PGE2, and VEGF [61]. Notably, PGE2 suppresses the activation and activity of T cells by enhancing PD-L1 expression and the polarization of TAMs through cAMP and mitochondrial signals, thereby forming a positive feedback cycle [62, 63].

Growing evidence indicates that M2-like TAMs are crucial for advancing tumor development. Research has identified a link between the polarization of M2-like TAMs and the HGF/c-MET pathway. The production of significant lactate by tumor cells is due to glycolysis, which serves as an intermediary between tumor cells and TAMs, thereby enhancing M2-like polarization through hypoxia-inducible factor 1α (HIF1α) [64]. Research by Jiang et al. revealed that the subsequent PI3K/AKT/mTOR pathway in the HGF/c-MET pathway controls VEGF and HIF-2 levels through the activation of HDM1 [65]. As a result, irregular stimulation of the HGF/c-MET pathway could enhance M2-like TAM polarization through the control of HIF-2 expression. Conversely, scientists have transformed M0-type macrophages into M1-like ones using interferon-gamma (IFN-γ) and LPS, observing a notable increase in c-MET expression in M1 macrophages. Moreover, administering HGF to M1 macrophages markedly triggers c-MET phosphorylation [66]. Subsequent research uncovered that the HGF-MET signaling pathway triggers the PI3K pathway, which in turn triggers Arg-1 expression in a dependent manner, propelling M1 macrophages to adopt an M2-like phenotype [66]. Furthermore, Wang et al. proposed that an excess of MET might directly stimulate TAMs through STAT3 phosphorylation, thereby encouraging M2-like TAM movement. Patients with GBM, characterized by an abundance of M2-like TAMs, showed notably reduced survival rates compared to those lacking macrophages [67]. Miagkova et al. discovered a link between MET and β-catenin in the cellular membrane of hepatocellular carcinoma (HCC). When stimulated by HGF, MET initiates the phosphorylation of β-catenin at tyrosine sites, causing its separation from MET and subsequent movement to the nucleus. This leads to the activation of Wnt target genes, which, in turn, encourages the growth, invasion, and spread of HCC [68, 69]. Other studies additionally uncovered that the Wnt/β-catenin pathway in liver cancer cells, through its subsequent target gene c-Myc, fosters M2-like TAM polarization [70, 71].

To sum up, the aggregated results of these previous studies suggest that irregular stimulation of the HGF/c-MET signaling route fosters M2-like TAM polarization, which in turn propels tumor expansion, movement, and spread.

MDSCs

MDSCs are a diverse collection of cells originating from the bone marrow, and are known for their strong immunosuppressive properties. These cells are crucial for maintaining the balance of tissues when faced with various systemic injuries such as infections and traumatic stress [72]. In the TME, MDSCs play a crucial role in the immunosuppressive network, collaborating with M2-like TAMs and CD4 + T cells to produce adverse regulatory impacts on the immune reaction. MDSCs interfere with immune monitoring through various mechanisms, such as inhibiting DCs from presenting antigens, suppressing T-cell activation, altering M1 macrophages, and blocking the cytotoxic effects of NK cells [73,74,75]. Tumor locations attract MDSCs via chemotactic agents like CCL2 and CCL5. Upon reaching the tumor location, they emit molecules that regulate the immune system, like IL-1, IL-6, ROS, and NO, to inhibit the immune functions of cells including NK cells and cytotoxic T lymphocytes (CTLs) [76,77,78].

Several studies have shown that the HGF/c-MET pathway participates in the recruitment and increase of MDSCs through multiple ways, and then promotes tumor immune evasion. Firstly, as mentioned before, the migration of MDSCs towards cancer cells is mainly regulated by CCL2 and CCL5. In a study on HCC, we were pleasantly surprised to find that the HGF/c-MET pathway and FGF19/FGFR4 collaboratively enhance ETV4 expression in HCC cells via the ERK1/2 axis, where ETV4, an ETS transcription factor upregulated in all HCC stages, increases PD-L1 and CCL2 expression, resulting in MDSCs and TAMs infiltration, CD8 T cells suppression and HCC metastasis [79, 80]. Mesenchymal stromal cells (MSCs), which are versatile progenitor cells with immune-modulating traits, are recognized for their capacity to inhibit the growth and activity of CD4 and CD8 lymphocytes, as well as for their release of immunosuppressive substances. Research has shown that stimulation of the HGF/MET signaling pathway may contribute to the proliferation of MDSCs by MSCs [