FCER1G: A multifunctional regulator in the immune microenvironment (Review)

1. Introduction

The Fc fragment of IgE receptor 1G (FCER1G) gene, mapping to chromosome 1q23.3, encodes the immunoglobulin Fc receptor common γ chain (FcRγ), an integral signaling adaptor in innate and adaptive immunity (1). Initially identified as the third subunit of the high-affinity IgE receptor complex (also known as FcεRIγ), FcRγ is currently recognized as a universal submit for multiple immunoreceptors. It severs as an essential signaling partner for Fc fragment of IgG receptor (FcγRI) (CD64), FcγRIII (CD16) and FcαRI (CD89), as well as for partner recognition receptors, including Dectin-1, Dectin-2 and the natural killer (NK) cell receptor NKp46 (2,3). Via its highly conserved intracellular immunoreceptor tyrosine-based activation motif (ITAM), FcRγ orchestrates canonical immune processes, including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent phagocytosis (ADCP), antifungal defense and inflammatory modulation (4,5).

Accumulating evidence has established FCER1G as a central regulator linking immune signaling to disease pathogenesis. In inflammatory diseases, its expression is tightly controlled by epigenetic mechanisms. Functionally, the protein displays distinct context-dependent effects: It can exacerbate vascular inflammation by polarizing immune cells toward a pro inflammatory phenotype, while it also regulates inflammatory intensity and promotes pathogen clearance during infection (6). This bidirectional regulation parallels mechanisms underlying tumor immune evasion, offering clues to its role in the tumor microenvironment (TME).

In oncology, FCER1G exhibits remarkable tissue-specific heterogeneity. Pan-cancer analyses show that its expression is elevated across numerous malignancies, primarily within monocyte and macrophage populations in the TME, and correlates strongly with immune checkpoint genes (1). In solid tumors such as renal cell carcinoma and gastric cancer, high FCER1G expression predicts poor prognosis by fostering an immunosuppressive microenvironment (7,8). Conversely, in hematologic malignancies such as multiple myeloma (MM) and in endometrial carcinoma, it may play a protective role (9,10). Mechanistically, FCER1G drives tumor progression by modulating immune suppression, promoting angiogenesis and regulating metastasis-related factors. It also influences the efficacy of antibody-based therapies through its role in antibody-dependent ADCC and ADCP.

Although no current drugs directly target FCER1G, several approved agents, such as kinase inhibitors, can indirectly modulate its activity by influencing upstream or downstream signaling nodes or altered ligand-receptor interactions, providing potential therapeutic opportunities (11). In summary, elucidating the mechanisms by which FCER1G governs inflammatory and oncogenic processes will deepen the current understanding of immune adaptor signaling in disease, and support the development of FCER1G-based biomarkers and targeted immunotherapies.

2. Molecular structure of FCER1G

The FcRγ protein encoded by FCER1G is a core component of the FcεRI complex (Fig. 1A). FcεRI exists as either a tetramer (αβγ2) or a trimer (αγ2). The FcεRIα chain contains two extracellular Ig-like domains that bind individual IgE molecules, thereby mediating IgE recognition (2). The FcεRIβ chain facilitates the maturation and trafficking of FcεRIα, and stabilizes the FcεRI complex on the cell surface (12). FcRγ is a small protein with a molecular weight of 15-20 kDa. Its extracellular domain is remarkably short, contains a conserved cysteine residue (Cys25) and forms homodimers via disulfide bonds, thereby constituting the essential signaling subunit of FcεRI (Fig. 1B) (2,13).

Figure 1 Protein structure of FCER1G and FcεRI schematic structure. (A) Protein structure of FCER1G [source: GeneCards database (https://www.genecards.org/)]. In the figure, blackish-brown represents the FcRγ subunit; bronze-gold represents the FcεRIβ subunit; green represents the FcεRIα subunit; brown represents the immunoglobulin heavy constant epsilon; and pink and bluish-purple represent the immunoglobulin kappa region. (B) Structural diagram of the FcεRI receptor. The FcεRIα chain binds individual IgE molecules, thereby mediating for IgE recognition. The FcεRIβ chain facilitates the maturation and trafficking of FcεRIα and stabilizes the FcεRI complex on the cell surface. FcRγ contains an ITAM motif; two molecules of FcRγ assemble with FcεRIα and FcεRIβ chains to form a complete tetrameric high-affinity IgE receptor. The figure was drawn with FigDraw2.0 (supplied by Hangzhou Sifei Technology Co., Ltd.). FCER1G, Fc fragment of IgE receptor 1G; FcεRI, Fc ε receptor I; ITAM, immunoreceptor tyrosine-based activation motif.

In addition to FcεRI, FcRγ also serves as an indispensable signaling adaptor for various Ig Fc receptors. These include the high-affinity IgG receptor FcγRI, involved in ADCP and ADCC, the low-affinity IgG receptor FcγRIII, which mediates ADCC in NK cells, and the IgA receptor FcαRI, a key regulator of neutrophil inflammatory responses. FcRγ further associates with pattern recognition receptors (PRRs) such as Dectin-1 and Dectin-2, as well as with the NK cell-activating receptor NKp46, playing a vital role in innate immune recognition.

3. Immunological function and signaling mechanisms of FCER1G

FcRγ is a crucial signaling adaptor protein within the immune system. It lacks intrinsic ligand-binding capacity, with its function entirely dependent upon a highly conserved ITAM within its intracellular domain. As a universal signaling subunit for multiple Ig Fc receptors (such as FcεRI and FcγR) and PRRs [such as C-type lectin receptors (CLRs)], FcRγ initiates downstream signaling cascades via its ITAM, thereby participating in regulating core immune processes, including allergic reactions, anti-infective immunity, and ADCC. Crucially, the biological effects of FcRγ are not uniform but exhibit distinct cell-type specificity. This specificity arises from its association with different receptors and the inherent differences in cellular signaling networks, enabling the same FcRγ-ITAM module to be programmed in diverse immune cells to execute differentiated functional programs.

Signal transduction and functional programming of FcRγ in different immune cells. Mast cells and basophils: FcεRI-mediated immediate hypersensitivity reactions

On the surfaces of mast cells and basophils, FcRγ constitutes the core component of the high-affinity IgE receptor FcεRI, forming a tetrameric (αβγ2) complex (14). Upon cross-linking of the receptor by an allergen-IgE complex, the ITAM of FcRγ rapidly recruits spleen tyrosine kinase (SYK), subsequently phosphorylating it. SYK-activated phospholipase Cγ (PLCγ) hydrolyses phosphatidylinositol bisphosphate to generate inositol trisphosphate (IP3) and diacylglycerol (14,15). IP3 subsequently induces intracellular calcium mobilization and extracellular calcium influx, triggering the rapid degranulation of stored mediators such as histamine and tryptamine, which are hallmarks of immediate-type allergic reactions (Fig. 2) (14,15). Knockout of the FCER1G gene prevents IgE-induced mast cell activation and allergic responses in mice (16). This research indicated that FcRγ protein stability is critical for its signaling function (16). For instance, the deubiquitinating enzyme USP5 stabilizes FcRγ by specifically removing K48-linked ubiquitin chains, thereby significantly enhancing IgE-induced mast cell activation and allergic inflammation, while inhibiting USP5 attenuates this process (17). This reveals that targeting FcRγ protein stability represents a novel pathway for regulating allergic responses.

Figure 2 Divergent intracellular signaling and functional mechanism mediated by FcRγ in different innate immune cells. Upon engagement of distinct ligand-receptor complexes (allergen-IgE complex, fungal α-mannan-Dectin-2, IgG-CD16A, IgG-CD64A), signaling is initiated via the associated FcRγ subunit, and phosphorylation of its ITAM recruits and activates SYK. This common initiating module then diverges into cell-type-specific downstream pathways, leading to distinct functional outputs in mast cells, natural killer cells, DCs and macrophages. The figure was drawn with FigDraw2.0 (supplied by Hangzhou Sifei Technology Co., Ltd.). FcR, Fc receptor; ITAM, immunoreceptor tyrosine-based activation motif; SYK, spleen tyrosine kinase; PLCγ, phospholipase Cγ; PIP2, phosphatidylinositol bisphosphate; IP3, inositol trisphosphate; DAG, diacylglycerol; DC, dendritic cell; ADCC, antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent phagocytosis; Th, T helper; ROS, reactive oxygen species.

Dendritic cells (DCs): Multireceptor-mediated antigen uptake and immune regulation. The function of FcRγ in DCs exhibits greater diversity and regulatory capacity than in mast cells and basophils, contingent upon the reprogramming of signals from the bound receptor complex FcεRI. The FcεRI expressed by DCs typically adopts a trimeric structure lacking the β chain (αγ2) (14). This structural difference leads to functional reprogramming, shifting from rapid effector responses towards antigen capture and presentation. In allergic diseases such as atopic dermatitis (AD), upregulation of FcεRI on cutaneous DCs enables efficient internalization of allergens upon IgE binding. These DCs then migrate to lymph nodes, primarily initiating T helper (Th)2-type immune responses, which is an important mechanism in conditions such as AD (14).

For CLRs lacking intracellular signaling domains, such as Dectin-2, FcRγ serves as an indispensable signaling partner. Upon recognizing fungal α-mannan, Dectin-2 activates SYK via the ITAM of FcRγ (18,19). This subsequently activates the NF-κB pathway through the CARD9-BCL10-MALT1 junction complex, driving cytokine production (including IL-6 and IL-23) and promoting Th17 differentiation (Fig. 2) (18,19). This is a critical component of antifungal immunity.

Previous research indicates that FcRγ also exerts negative regulatory effects on DCs. For instance, upon binding to Dectin-1 bearing a semi-ITAM, it may attenuate signal output by recruiting phosphatases such as SHP-1 and PTEN (16). This finely tunes DC maturation and cytokine production, preventing excessive inflammation (Fig. 2). This demonstrates that FcRγ in DCs functions not only as a transmitter of activation signals but also as a precise regulator of immune responses.

NK cells: CD16A (FcγRIIIA) signaling and antibody-dependent cytotoxicity. Within NK cells, FcRγ primarily functions as the signal-adaptor subunit for the low-affinity IgG receptor CD16A (FcγRIIIa). Their binding is essential for the stable expression and functional activity of this receptor on the cell surface. Upon NK cell recognition of tumor cells coated with antibodies (namely therapeutic monoclonal antibodies) via CD16A, phosphorylation of the ITAM recruits and activates SYK. Signaling in NK cells predominantly activates the SYK/PI3K-δ/MAPK axis (20). This pathway drives cytoskeletal reorganization as well as polarization and release of cytotoxic granules-a process involving the directed trafficking of perforin- and granzyme-containing vesicles toward the immune synapse - and promotes IFN-γ production, thereby efficiently executing ADCC (Fig. 2) (20). This constitutes a key mechanism underpinning the efficacy of numerous antibody therapeutics. This study indicates that de-fucosylated antibodies, by enhancing CD16A binding, significantly amplify downstream signaling through SYK/PI3K/MAPK and other pathways, thereby enhancing ADCC efficiency (4). Consequently, the functional state of FCER1G directly influences the efficacy of monoclonal antibody-based tumor immunotherapies.

Macrophages: Integrated signaling regulates phagocytosis, polarization and inflammatory balance. The function of FcRγ in macrophages integrates effector and regulatory roles, reflecting their immunological multifunctionality. As a signal-transducing subunit of receptors such as FcγRI (CD64), FcγRγ plays a pivotal role in mediating ADCP. Following immune complex cross-linking of FcγR, SYK activated by FcRγ-ITAM synergistically initiates multiple downstream pathways, including PLCγ, PI3K and MAPK (5). These collectively regulate actin remodeling, phagosome maturation and reactive oxygen species production, which is essential for phagocytosis, thereby efficiently eliminating antibody-coated targets (Fig. 2) (5).

Regarding bidirectional regulation of inflammatory phenotype and function, FcRγ signaling serves as a pivotal node in modulating macrophage polarization and inflammatory homeostasis. For instance, in atherosclerosis models, immune complexes activate FcγR to drive macrophage polarization towards a pro-inflammatory M1-like phenotype (21). This activates the NF-κB pathway, and leads to substantial release of inflammatory mediators such as TNF-α and IL-6, exacerbating plaque instability and vascular inflammation (21). Conversely, FCER1G deficiency predisposes macrophages towards an anti-inflammatory M2-like phenotype, mitigating disease progression (21). This demonstrates the pivotal role of FcRγ in determining macrophage functional output.

Other cell types and functions. FcRγ also participates in other immune processes, such as acting as a co-signaling chain for the collagen receptor GPVI in platelets to mediate thrombosis, and stabilizing cell surface receptors in type 3 innate lymphoid cells (ILC3s) to promote IL-22 production to combat infections (22,23). Its extensive involvement further underscores its importance as a universal ITAM-binding adaptor protein. FcRγ also functions as a signaling partner for myeloid receptors such as OSCAR and TREM-1, playing roles in several processes such as osteoclast differentiation and inflammatory amplification (24,25).

Common mechanisms and differentiation basis of FcRγ signaling

Despite varying functions across different cell types, the molecular mechanisms initiating FcRγ signaling remain highly conserved. Ligand-induced receptor clustering leads to mutual phosphorylation and activation of adjacent Src family kinases, which subsequently phosphorylate two tyrosine residues on the FcRγ-ITAM. The doubly phosphorylated ITAM recruits and activates SYK with high affinity, establishing SYK as the central hub for downstream signal differentiation (13,26).

From SYK, signals diverge into at least three primary pathways, with cells selectively amplifying specific pathways according to their functional predisposition: i) The PLCγ/Ca²+ pathway, which drives rapid degranulation responses in effector cells such as mast cells; ii) the PI3K/MAPK pathway, which predominantly governs ADCC/ADCP, cell migration, cell proliferation, and partial cytokine synthesis in NK cells and macrophages; and iii) the CARD9/NF-κB pathway, which predominantly governs transcriptional activation of pro-inflammatory cytokines and chemokines in DCs, macrophages and other cells following pathogen recognition via CLRs.

Therefore, FcRγ functions as a universal signaling molecule, receiving initial signals from upstream receptor clusters via its ITAM module and subsequently diverting these signals through SYK. Its ultimate functional output is co-programmed by the specific receptor it binds to and the downstream signaling network preferences dictated by the host cell type. This characteristic of ‘common mechanism, differential programming’ provides the molecular basis for understanding how FcRγ serves distinct roles across diverse pathological contexts, including allergy, infection, autoimmunity and even tumorigenesis, while also offering a logical explanation for its paradoxical dual function within the TME.

4. Immunoregulatory role of FCER1G in inflammatory diseases

Previous studies have revealed the multifaceted pathological roles of the innate immunity-related FCER1G gene. In non-neoplastic diseases, this gene contributes to the pathogenesis of inflammatory disorders such as eczema and AD (27-31).

Multilayered epigenetic regulation of FCER1G expression. The expression of FCER1G undergoes intricate and multilevel epigenetic regulation, forming a crucial molecular basis for its abnormal expression and functional plasticity in disease. In inflammatory conditions, DNA methylation emerges as a central regulatory mechanism controlling its expression, offering a relatively clear framework for understanding its functional regulation (Fig. 3).

Figure 3 Examples of epigenetic regulation of FCER1G in inflammatory diseases. In AD, the cytokine TSLP induces active demethylation of FCER1G by activating STAT5 and recruiting the demethylase TET2 to the FCER1G promoter region, thereby upregulating FCER1G expression and exacerbating allergic responses. In female patients with Vogt-Koyanagi-Harada disease, hypermethylation of the FCER1G promoter region in CD4+ T cells leads to gene silencing and is associated with glucocorticoid resistance. The figure was drawn with FigDraw2.0 (supplied by Hangzhou Sifei Technology Co., Ltd.). FCER1G, Fc fragment of IgE receptor 1G; TSLP, thymic stromal lymphopoietin; TSLPR, thymic stromal lymphopoietin receptor; AD, atopic dermatitis; TET2, ten-eleven translocation 2; STAT5, signal transducer and activator of transcription 5; APCs, antigen-presenting cells; FcRγ, Fc receptor common γ chain; p, phosphorylation.

Dynamic regulation of DNA methylation/demethylation. DNA methylation constitutes a core epigenetic mechanism in the regulation of FCER1G expression. Previous studies have shown a significant inverse correlation between the methylation status of CpG islands in the FCER1G promoter region and its expression levels (28,32-35). In patients with AD, monocytes exhibit specific hypomethylation of the FCER1G promoter, which directly upregulates its mRNA and protein levels. This consequently causes overexpression of receptors such as FcεRI on antigen-presenting cell (APC) surfaces, exacerbating allergic reactions (28). This causal association has been directly validated by patch methylation combined with luciferase reporter assays (28,36).

In rheumatoid arthritis, FCER1G also displays a pattern of high expression associated with hypomethylation (33,34). Similarly, in female patients with Vogt-Koyanagi-Harada disease, hypermethylation of the FCER1G promoter in CD4+ T cells silences its expression, enhancing patient resistance to cyclosporine A and corticosteroids (32). This suggests that intervention targeting the methylation status of the FCER1G promoter may represent a potential therapeutic sensitization strategy.

Synergistic interaction between key transcription factors and demethylases: The demethylation of FCER1G is driven by specific cytokine signals through an active mechanism involving transcription factor-mediated recruitment of DNA demethylases. Within the pathological environment of AD, thymic stromal lymphopoietin (TSLP) produced by epithelial cells serves as the key driver. TSLP activates its receptor, leading to signal transduction and the phosphorylation of signal transducer and activator of transcription 5 (STAT5) (29,37). Activated phosphorylated (p)-STAT5, acting as a transcription factor, is recruited to the FCER1G promoter region, simultaneously recruiting the DNA demethylase ten-eleven-translocation 2 (TET2), which catalyzes the conversion of 5-methylcytosine to 5-hydroxymethylcytosine, thereby initiating an active demethylation program that relieves the transcriptional repression of FCER1G (29,37). This TSLP/p-STAT5/TET2 axis forms a coherent epigenetic reprogramming pathway, explaining the epigenetic basis for the sustained high expression of FCER1G in AD.

Regulation through chromatin plasticity by transcription factors. In addition to the aforementioned core mechanisms, the regulation of chromatin plasticity by specific transcription factors also contributes to the control of FCER1G expression. For instance, in hematopoietic stem cells (HSCs), the transcription factor Bcl11a directly represses FCER1G transcription by suppressing chromatin accessibility at its promoter region, a process that is critical for maintaining HSC quiescence (38). This mechanism illustrates how transcription factors can precisely control FCER1G expression at the epigenetic level by modifying chromatin architecture.

The aforementioned complex epigenetic regulatory mechanisms determine that FCER1G expression exhibits a high degree of microenvironmental dependency and dynamic plasticity. This characteristic enables it to perform differentiated roles across distinct pathological contexts, where both its expression levels and functional outputs (pro-inflammatory or anti-inflammatory) must be interpreted within specific diseases (39-41).

Context-dependent regulation of FcRγ in anti-infection immunity

In anti-infection immunity, the FcRγ exhibits a dual function, with its presence or absence influencing pathogen clearance and host prognosis differently across various infection models, thus profoundly demonstrating its context-dependent nature. In a chronic lymphocytic choroid plexus meningitis virus infection model, FcRγ expressed in NK cells delays pathogen clearance by suppressing virus-specific CD8+ T-cell responses (6). In addition, deletion of FcRγ significantly reduces mortality in mouse models of sepsis induced by lipopolysaccharide or Escherichia coli, which is characterized by lower serum levels of TNF-α, IL-6 and IL-10(39). These models suggest that, under certain circumstances, FcRγ-mediated signaling may prove detrimental to infection control or host survival by promoting excessive inflammation or suppressing adaptive immunity. However, in other infection models, FcRγ plays an indispensable role in defensive mechanisms. Conversely, the absence of FcRγ in ILC3s impairs JAK-STAT pathway activation and reduces IL-22 and IL-17A secretion, thereby increasing mortality during fungal infection (22). Similarly, during Pneumocystis pneumonia, FcRγ deficiency decreases the production of inflammatory cytokines (TNF-α, IL-6 and IL-1β) but compromises pathogen clearance efficiency (40). This indicates that FcRγ-mediated immune responses are essential for the effective clearance of the aforementioned pathogens.

The dual outcomes of FcRγ during infection (beneficial or detrimental) are likely determined by two major factors. On the one hand, the type of pathogen and the nature of the infection are critical. For intracellular chronic viruses (such as lymphocytic choriomeningitis virus) or systemic bacterial toxins (sepsis), excessive inflammation or inappropriate immune regulation may lead to immunopathology or tissue damage, where FcRγ activity often contributes to detrimental outcomes. Conversely, combating certain fungi and opportunistic pathogens (such as Pneumocystis) necessitates FcRγ-dependent rapid initiation of innate immune effector programs in specific cells (namely ILC3s), where its function is beneficial. On the other hand, maybe the dominant immune cells and effector mechanisms govern the response. FcRγ's function is entirely dependent on its cellular environment. In NK cells, it may modulate immune crosstalk, occasionally suppressing T cell function, whereas, in ILC3s, it directly stimulates antimicrobial cytokine production. Thus, the cell type dictates whether FcRγ-mediated signaling leads to inhibitory regulation or effector activation.

In summary, the presence of FcRγ is not inherently positive or negative in infectious immunity. Instead, its value depends on the immune equilibrium set by the specific infection microenvironment. FcRγ dynamically modulates the intensity and quality of immune responses by influencing two critical balances: i) Pro-inflammation vs. anti-inflammation and ii) immune activation vs. suppression. This capacity for flexible role-switching in response to microenvironmental signals and precise regulation of immune balance bears striking similarity to the functional plasticity of immune checkpoint molecules within the TME, and provides a core logical framework for understanding the complex role of FCER1G in tumor immunity.

5. Expression of FCER1G in tumors

Pan-cancer expression profile and characteristics associated with the immune microenvironment

Pan-cancer analysis based on the TIMER 2.0 database (https://compbio.cn/timer2/) shows that FCER1G is significantly upregulated in 9 types of malignant tumor compared with normal tissues (Fig. 4). These include esophageal carcinoma, glioblastoma multiforme (GBM), head and neck squamous cell carcinoma, kidney clear cell carcinoma, kidney papillary cell carcinoma, stomach adenocarcinoma (STAD) and thyroid carcinoma. Gene enrichment analyses further reveal that FCER1G is predominantly involved in cell proliferation-related pathways across multiple tumor types, particularly STAD, TGCT, acute myeloid leukemia and GBM (P<0.05, false discovery rate <0.25) (41). Furthermore, FCER1G expression positively correlates with >50% of immune checkpoint genes, suggesting that it functions as a hub regulator within the tumor immunoregulatory network (41). Single-cell transcriptomic data from the TISCH database indicate that FCER1G is preferentially expressed in monocyte/macrophage populations within the TME across ~85% of the tumors analyzed, thus providing cellular-level evidence for its involvement in TME remodeling.

Figure 4 Expression of FCER1G across 33 cancer tissue types and 21 paired normal tissues based on the TIMER2.0 database (*P<0.05, **P<0.01 and ***P<0.001). The figure was from the TIMER2.0 database (https://compbio.cn/timer2/). FCER1G, Fc fragment of IgE receptor 1G; TPM, transcripts per million. ACC, adrenocortical carcinoma; BLCA, bladder urothelial carcinoma; BRCA, breast invasive carcinoma; CESC, cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOL, cholangiocarcinoma; COAD, colon adenocarcinoma; DLBC, diffuse large B-cell lymphoma; ESCA, esophageal carcinoma; GBM, glioblastoma multiforme; HNSC, head and neck squamous cell carcinoma; KICH, kidney chromophobe; KIRC, kidney renal clear cell carcinoma; KIRP, Kidney Renal Papillary Cell Carcinoma; LAML, acute myeloid leukemia; LGG, brain lower grade glioma; LIHC, liver hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; MESO, mesothelioma; OV, ovarian serous cystadenocarcinoma; PAAD, pancreatic adenocarcinoma; PCPG, pheochromocytoma and paraganglioma; PRAP, prostate adenocarcinoma; READ, rectum adenocarcinoma; SARC, sarcoma; SKCM, skin cutaneous melanoma; STAD, stomach adenocarcinoma; TGCT, testicular germ cell tumors; THCA, thyroid carcinoma; THYM, thymoma; UCEC, uterine corpus endometrial carcinoma; UCS, uterine carcinosarcoma; UVM, uveal melanoma.

Dual nature of tissue-specific expression patterns and prognostic value. FCER1G expression correlates with poor prognosis in tumors

Comprehensive analysis indicates that FCER1G is highly expressed in multiple solid tumors, including clear cell renal cell carcinoma (ccRCC) (presented as KIRC in Fig. 4), esophageal squamous cell carcinoma (ESCC) (included within the esophageal cancer group when presented in Fig. 4) and STAD (7,8,42) (Fig. 4). Its expression is predominantly enriched in myeloid immune cells, where it promotes the formation of an immunosuppressive microenvironment, thereby contributing to poor prognosis.

Data from the Human Protein Atlas (HPA) show markedly stronger immunohistochemical staining of FCER1G in renal carcinoma tissues than in adjacent normal tissues (Fig. 5). According to Wang et al (7), analysis of the ONCOMINE database and three validation datasets identified significantly elevated FCER1G expression in ccRCC, where high expression correlated with reduced overall survival (OS). Similarly, Dong et al (43) observed that, in ccRCC, FCER1G expression exhibited a strong correlation with CD68 and co-localization with macrophages. Their concurrent overexpression portends an unfavorable prognosis. Joint assessment of FCER1G and CD68 expression levels can optimize prognostic stratification models for patients. Furthermore, gene set enrichment analysis revealed that high FCER1G expression is associated with suppression of T-cell activation and proliferation (43). FCER1G shows moderate diagnostic accuracy (area under the curve, 0.74) in distinguishing localized (stage I/II) from advanced (stage III/IV) ccRCC, and functions as an independent prognostic biomarker (44).

Figure 5 FCER1G protein is highly expressed in ccRCC tissues. Immunohistochemical staining from the Human Protein Atlas database revealed significantly elevated FCER1G expression in ccRCC tissue compared with that in normal renal tissue (increased staining intensity and proportion of positive cells). The normal kidney sample corresponds to a 16-year-old male donor (sample ID, 1,767; staining, medium; intensity, low; quantity of FCER1G-positive cells <25%; location of FCER1G protein, nuclear), while the renal cancer sample corresponds to a 70-year-old female patient with ccRCC (sample ID, 1,498; staining, medium; intensity, medium; quantity of FCER1G-positive cells >75%; location of FCER1G protein, nuclear). This figure is from the public database HPA (Human Protein Atlas), for which patient consent for publication is not required in accordance with the database's usage guidelines (https://www.proteinatlas.org/). Scale bar, 200 µm. FCER1G, Fc fragment of IgE receptor 1G; ccRCC, clear cell renal cell carcinoma.

In ESCC, FCER1G is predominantly enriched within the tumor stroma. Double immunofluorescence staining clearly demonstrates that FCER1G-positive cells highly co-express the M2 macrophage marker CD163, meaning that the majority of infiltrating M2 macrophages simultaneously express FCER1G (42). The infiltration density of these FCER1G+ M2 macrophages correlates directly with worse prognosis, and FCER1G itself constitutes an independent risk factor affecting patients' OS (42). In STAD, analyses from multiple transcriptomic cohorts (The Cancer Genome Atlas, GSE13195 and GSE15459) consistently showed higher FCER1G expression in tumor tissues than in adjacent normal tissues (8,41,45). Its overexpression is linked to poorer OS and increased infiltration of M2 macrophages (8). Furthermore, FCER1G expression progressively increases with advancing tumor stage, suggesting a dynamic upregulation trend during tumor progression. This finding, similar to that observed for ESCC, suggests that FCER1G may be primarily expressed in M2-type tumor-associated macrophages (TAMs) within STAD and participate in shaping the immunosuppressive microenvironment.

Additionally, in gliomas, diffuse large B-cell lymphoma, bladder cancer and papillary thyroid carcinoma, FCER1G acts as a progression-associated gene, where high expression of FCER1G correlates with aggressive tumor behavior, poor prognosis and distinct immune infiltration patterns (11,46-51). In osteosarcoma, a dual-gene risk model incorporating FCER1G and SPI1, developed based on Cox regression analysis, holds independent prognostic significance. Patients in the low-expression group for this signature exhibit an immunosuppressive microenvironment, worse clinical outcomes and a higher risk of metastasis, highlighting the potential of FCER1G as a prognostic biomarker and immunotherapeutic target (52). It is noteworthy that bioinformatics analysis suggests that FCER1G may be a hypermethylated gene in osteosarcoma, offering a potential epigenetic hypothesis to explain its low expression in this tumor type. However, the precise regulatory mechanisms require experimental validation (35).

In summary, FCER1G is highly expressed in multiple solid tumors, including ccRCC, ESCC, STAD and glioma. By promoting M2 macrophage infiltration and shaping an immunosuppressive TME, it contributes to tumor progression and serves as a consistent indicator of poor prognosis across various cancer types (Table I).

Table I Expression patterns, cellular types, prognostic correlations and immune microenvironment characteristics of FCER1G in different tumors.

Table I

Expression patterns, cellular types, prognostic correlations and immune microenvironment characteristics of FCER1G in different tumors.

Tumor	FCER1G expression	Prognosis	Primary cell types expressing FCER1G	Key associated immune cells/ pathways
ccRCC	Upregulated	Poor	Tumor-associated macrophages	Co-expressed with CD68, associated with suppression of T-cell activation
ESCC	Upregulated	Poor	M2 macrophages	Positively correlated with CD163+ M2 macrophage infiltration
STAD	Upregulated	Poor	Hematopoietic immune cells (such as macrophages)	Associated with enhanced M2 macrophage infiltration
MM	Downregulated	Favorable	NK and other effector immune cells	Associated with NK cell-mediated cytotoxicity pathway
UCEC	Downregulated	Favorable	Multiple immune cells (including B, CD8+ T and dendritic cells)	Associated with increased infiltration of B, CD8+ T and other cells

[i] FCER1G, Fc fragment of IgE receptor 1G; ccRCC, clear cell renal cell carcinoma; ESCC, esophageal squamous cell carcinoma; STAD, stomach adenocarcinoma; MM, multiple myeloma; UCEC, uterine corpus endometrial carcinoma; NK, natural killer.

FCER1G correlates with favorable patient prognosis. In contrast to its generally pro-tumor pattern, FCER1G displays a protective role in certain malignancies, where high expression is associated with prolonged survival and enhanced immune activation. In MM, analyses of several datasets (including GSE39754, GSE5900 and GSE2113) reveal a progressive decline in FCER1G expression with disease advancement (9,53). Multivariate Cox regression analysis identifies high FCER1G expression as an independent predictor of both event-free survival and OS, establishing it as a favorable prognostic biomarker in MM (9). Furthermore, FCER1G overexpression correlates with NK cell-mediated cytotoxic pathways (9). Notably, previous research has identified a functionally distinct FcεRIγ- NK cell subset (termed g-NK cells) (54). Compared to conventional NK cells, these cells exhibit enhanced ADCC following CD16 cross-linking and significantly amplify the efficacy of monoclonal antibodies such as daratumumab in preclinical models (54). This offers a novel perspective on the association between FCER1G expression in MM, NK cell function and favorable prognosis. Similarly, in uterine corpus endometrial carcinoma (UCEC), high FCER1G expression predicts improved prognosis, and correlates with increased infiltration of immune cells, including B cells, CD8+ T cells and DCs (Table I) (10).

In lung adenocarcinoma (LUAD), FCER1G expression exhibits stage-specific dynamics, being downregulated in early stages and restored at advanced stages (55). Network analyses further indicate that FCER1G consistently functions as an immune regulatory hub throughout LUAD progression, and that its functional loss impairs antitumor immune activity (55).

Overall, the prognostic significance of FCER1G shows clear tumor-type specificity.

In malignancies such as MM and UCEC, as well as in specific stages of LUAD, elevated FCER1G expression is not associated with tumor promotion. Instead, it may exert a protective effect by sustaining or activating antitumor immune responses, ultimately predicting more favorable clinical outcomes (Table I).

Contradictory prognostic value of FCER1G arises from heterogeneity in the TME. In summary, the prognostic value of FCER1G exhibits marked inconsistencies, fundamentally stemming from the cellular types expressing FCER1G, which determine the nature of the specific, coordinated immune processes in which it participates (Fig. 6).

Figure 6 Schematic diagram of the cytological basis for FCER1G prognostic paradox. The dual prognostic value of FCER1G is clearly demonstrated to depend on the cellular context in which it is expressed. Left pathway: When FCER1G is highly expressed in M2 TAMs, it promotes an immunosuppressive microenvironment, leading to poor prognosis. Right pathway: When FCER1G is highly expressed in effector immune cells such as natural killer cells, it enhances the antitumor immune response, which is associated with favorable prognosis. The figure was drawn with FigDraw2.0 (supplied by Hangzhou Sifei Technology Co., Ltd.). FCER1G, Fc fragment of IgE receptor 1G; TME, tumor microenvironment; TAMs, tumor-associated macrophages; ADCC, antibody-dependent cellular cytotoxicity.

Regarding its expression in immunosuppressive myeloid cells (pro-tumor function), in solid tumors such as ccRCC and ESCC, FCER1G is primarily expressed in M2-type TAMs. These cells shape an immunosuppressive TME by secreting immunosuppressive factors (such as IL-10 and TGF-β), depleting T cells and promoting angiogenesis. This drives tumor progression and immune evasion, leading to poor prognosis (42,43). Regarding its expression in cytotoxic cells or APCs (antitumor function), in tumors such as MM and UCEC, high expression of FCER1G correlates with the active state of effector cells or APCs, including DC, and NK, cytotoxic T and B cells. In this context, FCER1G functions as a signaling adaptor for activation receptors (CD16A) on these cells, participating in the initiation of antitumor immune responses such as ADCC and T-cell activation, thereby correlating with favorable prognosis (9,10,41).

Therefore, assessing the clinical relevance of FCER1G necessitates moving beyond mere expression levels to deeply analyze its cellular localization and the associated functional state of the overall immune microenvironment. This cellular context determinism lies at the core of understanding its complexity as a biomarker.

Core mechanisms driving tumor progression and immune remodeling. Regulation of immune microenvironment structure and function

FCER1G exhibits distinct immunoregulatory patterns across different tumor types. In STAD, its expression correlates positively with the infiltration of M1/M2 macrophages, quiescent mast cells and DCs, but negatively with plasma and CD8+ T cells (45). This opposing infiltration pattern indicates that FCER1G may facilitate tumor progression by reshaping an immunosuppressive immune microenvironment. In glioma, FCER1G expression is strongly associated with the infiltration of T cells, macrophages and B cells, further implicating it in disease progression and immune landscape remodeling (47). Notably, previous single-cell RNA sequencing studies have identified a tumor-specific, innate-like cytotoxic T-cell subset characterized by FCER1G+ αβTCR+ cells (56,57). FCER1G serves as a definitive lineage marker for this population. Unlike conventional tumor-reactive T cells, these cells recognize unmutated self-antigens presented by MHC-I molecules rather than tumor-derived neoantigens. Their intratumoral activation and effector functions depend strictly on the IL-15 signaling axis, underscoring a unique FCER1G-mediated mechanism of cytotoxic immune regulation within the TME (56,57).

This identification implies that FCER1G is not merely a participant in immunosuppression but also acts as a phenotypic identity tag for specific antitumor immune cell subsets, highlighting its multifaceted roles within the TME. Collectively, the evidence suggests that FCER1G possesses dual regulatory properties. It can promote immunosuppressive phenotypes in certain contexts while also functioning as a key regulatory node for antitumor responses in distinct immune populations. Dysregulation of its expression or signaling may therefore disrupt immune homeostasis and drive the pathological remodeling of the TME.

Supporting its functional relevance, analyses of the Gene Expression Profiling Interactive Analysis and HPA databases showed that FCER1G expression is significantly higher in PAAD tissues than in normal tissues at both the mRNA and protein levels. In animal models, FcRγ-deficient [FCER1G-/-, FcRγ knockout (KO)] mice bearing pancreatic ductal adenocarcinoma exhibit reduced tumor growth and attenuated desmoplasia, accompanied by a complete loss of FcγRI/III expression within tumors (58). These findings indicate that FCER1G likely modulates the TME and drives malignant progression through the regulation of Fc receptor-mediated signaling pathways.

Promotion of angiogenesis. Andreu et al (59), using an HPV16+/FcRγ-/- mouse model, revealed a key role for FcRγ in tumorigenesis. Compared with wild-type (WT) mice, FcRγ KO mice showed a lower incidence of SCC. This effect was associated with inhibited angiogenesis and decreased expression of major oncogenic factors, including vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) (59). Further experiments demonstrated that mast cells and macrophages promote endothelial cell migration via FcRγ-dependent pathways, thereby enhancing the in vivo tumorigenicity of the PDSC5 SCC cell line (59). Collectively, these findings indicate that FcRγ promotes tumor angiogenesis by mediating interactions between immune and stromal cells within the TME.

Promotion of tumor metastasis. The expression status of FCER1G is frequently implicated in tumor metastasis, although its effects vary among cancer types. In hepatocellular carcinoma (HCC), FCER1G shows a downregulated trend, and its low expression is associated with the activation of apoptotic and ferroptotic pathways (60). Previous in vitro experiments have shown that silencing FCER1G enhances the proliferation and migration of HCC cells by upregulating Snail1, TWIST1 and N-cadherin while suppressing E-cadherin expression (60). These results suggest that FCER1G may restrain HCC invasiveness by modulating epithelial-mesenchymal transition (EMT) processes.

In malignant melanoma (MEL), the role of FcRγ exhibits a more intricate profile, characterized by context-dependent effects. On the one hand, lung metastasis can be suppressed by treatment with the monoclonal antibody TA99 or intravenous Ig (IVIG) (61,62). This antimetastatic effect depends entirely on FcRγ, as it is abolished in FcRγ KO mice, indicating that ADCC serves as a key mechanism. On the other hand, FcRγ deficiency itself exerts dual and opposing effects on metastasis (Fig. 7). Specifically, the absence of FcRγ enhances platelet adhesion to circulating tumor cells, and stimulates platelets to release the chemokines C-X-C motif chemokine ligand (CXCL)5 and CXCL7. This cascade promotes neutrophil recruitment to lung tissue and creates a pro-transfer microenvironment that accelerates lung metastasis without affecting primary tumor growth (3).

Figure 7 Two mechanisms by which FcRγ deficiency promotes tumor lung metastasis in MEL: i) Enhances adhesion between platelets and circulating tumor cells, inducing platelets to release chemokines CXCL5/7 to recruit neutrophils and establish a pre-metastatic microenvironment; and ii) reduces the expression of CD244, a key maturation molecule for NK cells, thereby impairing NK cell function. The figure was drawn with FigDraw2.0 (supplied by Hangzhou Sifei Technology Co., Ltd.). MEL, malignant melanoma; NK, natural killer; FcRγ, Fc receptor common γ chain; CXCL, C-X-C motif chemokine ligand; NKG2, natural killer cell group 2; LY49, Lymphocyte Antigen 49 Complex; DNAM-1, DNAX Accessory Molecule-1.

Furthermore, FcRγ KO impairs CD244-mediated inhibitory signaling during NK cell development, leading to diminished NK cell function (63). This defect can be reversed by treatment with IL-2 or IL-15, which upregulates activation receptors [natural killer cell group 2 (NKG2)D and DNAX accessory molecule-1] and downregulates inhibitory receptors (LY49 and NKG2A), thereby restoring NK cell cytotoxicity and suppressing metastasis (63). Therefore, therapeutic strategies aimed at modulating FcRγ signaling must carefully balance the benefits of enhancing antibody-dependent tumor clearance against the potential risk of facilitating metastatic dissemination.

FcRγ-dependent therapeutic responses and resistance mechanisms. Essential role of the FcγRI/III signaling pathway

FcRγ serves as a critical molecular determinant for the efficacy of multiple antibody-based therapies. In colorectal cancer (CRC), FCER1G expression is paradoxically higher in adjacent non-tumorous tissues than in tumor tissues (64). Within this setting, IVIG treatment fails to produce antitumor effects in FcRγ KO mice. Mechanistically, the therapeutic activity of IVIG depends on FcγRI/III signaling, which drives the reprogramming of TAMs from an M2-like, pro-tumor state toward an M1-like, antitumor phenotype (64).

In adult T-cell leukemia/lymphoma (ATL) models, anti-CD2 monoclonal antibody MEDI-507 and anti-CD25 monoclonal antibodies significantly suppress tumor progression and prolong survival, with their efficacy strictly dependent on FcRγ (65,66). Specifically, polymorphonuclear leukocytes and monocytes eliminate CD2+/CD25+ tumor cells through FcγRIII-mediated ADCC (65,66). The absence of FcRγ disrupts this pathway, resulting in therapeutic resistance despite normal antibody pharmacokinetics.

It is noteworthy that not all antibody therapies rely on FcγR signaling. In anaplastic large-cell lymphoma (ALCL), the anti-CD30 monoclonal antibody HeFi-1 suppresses tumor growth primarily by inducing G1-phase cell-cycle arrest, thereby exerting its antitumor effect independently of FcγRIII expression (67).

In general, these findings underscore a crucial principle: For a broad range of antibody therapies targeting tumors such as CRC and ATL, the FcγRI/III signaling pathway represents an indispensable axis for antitumor efficacy. This pathway mediates the key effector functions of myeloid cells, including macrophages and neutrophils, in achieving therapeutic success.

Impact of drug intervention on the prognostic value of FCER1G. The prognostic importance of FCER1G in ccRCC appears to be treatment specific. It shows strong prognostic value in patients treated with the anti-PD-1 antibody nivolumab, but not in those receiving the mTOR inhibitor everolimus (43). This treatment-specific difference may reflect the regulatory role of FCER1G in modulating responses to immune checkpoint inhibitors such as nivolumab, whereas its association with mTOR pathway-targeted therapies appears to be relatively weak (41). Furthermore, pharmacological interventions can dynamically influence the immunoregulatory activity of FcRγ. For instance, peripheral blood NK cells from lung transplant recipients treated with rapamycin (an mTOR inhibitor) exhibit markedly reduced FcRγ expression. This observation suggests that drug-induced modulation of FcRγ may indirectly affect immune homeostasis and therapeutic outcomes (68).

6. Existing drugs indirectly regulating FCER1G-related pathways

Despite the pivotal role of FCER1G in multiple tumor immune microenvironments, no clinical drugs directly targeting this molecule currently exist. Through an integrated analysis of the DrugBank website and the DGIdb database, four classes of drugs have been identified that indirectly influence FCER1G-related pathways by regulating upstream and downstream signaling molecules (Table II). These include aspirin, benzylpenicilloyl polylysine, omalizumab and fostamatinib. For instance, omalizumab functions as an IgE monoclonal antibody. By blocking the binding of IgE to its high-affinity receptor FcεRI, it is widely employed in treating asthma and chronic spontaneous urticaria. Similarly, fostamatinib, as a SYK inhibitor, targets SYK, the core downstream signaling molecule of FcRγ. Although these drugs do not directly target FCER1G, their mechanisms of action demonstrate that intervention in pathways upstream (ligand-receptor binding) or downstream (ITAM signaling) of FCER1G can produce distinct biological effects.

Table II Candidate drugs that may indirectly modulate the FCER1G-associated signaling pathway.

Table II

Candidate drugs that may indirectly modulate the FCER1G-associated signaling pathway.

Potential drugs	Drug category	Status	Primary mechanism of action	Target
Aspirin	Nonsteroidal anti-inflammatory drug	Approved	Non-selective COX inhibitor	COX
Benzylpenicilloyl polylysine	Diagnostic reagent	Approved	FCER1A agonist	FCER1A
Omalizumab	Monoclonal antibody	Approved	IgE inhibitor	IgE
Fostamatinib	Small-molecule inhibitor	Approved	SYK inhibitor	SYK

[i] FCER1G, Fc fragment of IgE receptor 1G; COX, cyclooxygenase; SYK, spleen tyrosine kinase.

Although existing pharmacological agents offer valuable insights into modulating the ITAM-SYK pathway activated by FCRγ, directly targeting FCER1G for cancer therapy remains considerably challenging. Therefore, a more feasible current approach may be to leverage FCER1G not as a direct therapeutic target, but as a key interpretative factor for understanding tumor immune microenvironment heterogeneity and as a biomarker for patient stratification. For instance, evaluating FCER1G expression and its associated immune cell infiltration patterns could help identify patients most likely to benefit from antibody therapies or immune checkpoint inhibitors that rely on FcγR effects. Future research should elucidate the precise molecular switches determining whether FCER1G function shifts towards a pro-tumor or antitumor role across different tumor types. This is a prerequisite for its safe translation into an effective therapeutic target.

7. Conclusion and outlook

As a core signaling adaptor, FCER1G mediates activation signals for multiple immune receptors through its ITAM, playing an indispensable role in both innate and adaptive immune responses. The present review systematically summarizes the multidimensional functions of FCER1G, spanning fundamental immune regulation to its involvement in disease pathogenesis. Beyond its classical roles in allergic reactions and anti-infection immunity, FCER1G shows profound pathological importance in inflammatory diseases and tumors.

In inflammation, FCER1G expression is finely regulated by epigenetic mechanisms. Acting as a sensor of the immune microenvironment, it dynamically modulates the magnitude and outcome of inflammatory responses by influencing the polarization of immune cells such as macrophages. Its functional plasticity provides essential clues to its behavior within the more complex TME.

FCER1G is highly expressed in several malignancies, including ccRCC, STAD and GBM, and correlates positively with immune checkpoint molecules such as PD-L1, suggesting its role as a central immune regulatory hub. Its tumor-promoting mechanisms are multifaceted, manifested in the formation of an immunosuppressive milieu through M2 macrophage recruitment and limited CD8+ T-cell infiltration (as in STAD). FCER1G also mediates signaling crosstalk between FcγR and EMT pathways, thus shaping tumor-immune interactions. Beyond immunity, it participates in various non-immune regulatory processes, including angiogenesis (via VEGF/MMP-9 in SCC), platelet-mediated metastasis (via CXCL5/CXCL7 in MEL) and cell-cycle progression (in ALCL).

Clinically, the impact of FCER1G is context dependent. High expression predicts favorable prognosis in MM and UCEC, but correlates with poor outcomes in ccRCC and STAD, underscoring its tissue-specific prognostic importance. Furthermore, antibody therapies that rely on FcRγ show pronounced therapeutic efficacy in ATL and MEL models. Although several drugs targeting FCER1G-related pathways have been identified, such as aspirin and penicillanoyl polylysine (11), their translational value in oncology remains to be thoroughly investigated.

Despite substantial progress has been achieved in FCER1G research, several critical directions demand further investigation. Future studies should first prioritize elucidating the cross-cancer synergistic mechanisms between FCER1G and immune checkpoints (such as PD-1/PD-L1) as well as other immunoregulatory molecules, providing a conceptual basis for rationally designed combination therapies. Particular attention should be given to elucidating the molecular mechanisms underlying FCER1G's dual roles in promoting or suppressing tumor progression across distinct microenvironmental contexts. Additionally, clinical translation faces notable challenges, especially concerning the dose-dependent toxicity and limited tissue selectivity of existing FCER1G-related drugs (such as aspirin and penicillanoyl polylysine). Thus, well-designed, multicenter clinical trials are urgently needed to validate therapeutic efficacy and safety profiles of interventions targeting FCER1G or its associated pathways (FcγR and SYK) in both solid tumors and hematological malignancies.

Furthermore, optimizing therapeutic strategies through tissue-targeted drug delivery represents a promising avenue. Developing delivery systems capable of specifically targeting FCER1G-expressing immune subsets or tumor-associated stromal cells could improve treatment precision. Such strategies may also help minimize off-target effects and mitigate potential pro-metastatic risks such as unintended platelet activation, which can arise from the broad distribution of FcγRs.

In summary, as a multifunctional molecule with both fundamental immunological importance and translational potential, FCER1G represents a promising target for next-generation cancer immunotherapy. Continuous elucidation of its complex regulatory networks and development of innovative therapeutic strategies are expected to further expand its clinical value and ultimately improve patient outcomes.

Acknowledgements

Not applicable.

Funding

Funding: The present study was supported by the Science and Technology Program of Gansu Province (grant no. 23JRRA1015).

Availability of data and materials

Not applicable.

Authors' contributions

YZ and JW wrote the original draft. JW, WH and TL conceptualized the topic, reviewed and edited the review. All authors read and approved the final manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References