Targeting TNFRSF13B: Dual-Target Strategies Usher in New Focus for Treating Tumors and Autoimmune Diseases

1. Research Background of TNFRSF13B (TACI)

TNFRSF13B (Tumor Necrosis Factor Receptor Superfamily Member 13B), also known as TACI (Transmembrane Activator and CAML Interactor), is an important member of the TNF receptor superfamily. This gene is located on human chromosome 17p11.2, and its encoded TACI protein plays a core role in immune regulation, B cell homeostasis maintenance, and various disease processes. TACI can bind to APRIL (A Proliferation-Inducing Ligand) and BAFF (B Cell Activating Factor), regulating the proliferation, differentiation, and survival of B cells, and is crucial for maintaining humoral immune homeostasis ^[2,4].

Under normal conditions, TACI activation promotes B cell differentiation into plasma cells, facilitating immunoglobulin class switching and antibody production ^[2,6]. However, aberrant expression or mutation of TNFRSF13B can disrupt immune balance and is associated with various diseases, including Chronic Lymphocytic Leukemia (CLL), melanoma, Lupus Nephritis (LN), Multisystem Inflammatory Syndrome in Children (MIS-C), and Common Variable Immunodeficiency Disease (CVID) ^[1,4,6,7,8].

2. Mechanism of Action of TNFRSF13B (TACI)

2.1 Immunoregulatory Mechanism

The primary function of TNFRSF13B is to regulate B cell immune responses by binding to ligands such as APRIL and BAFF. In the inflammatory microenvironment, interaction between membrane-bound APRIL and TACI on the B cell surface can induce macrophages to release inflammatory mediators like IL-8 and MMP-9, promoting chronic inflammation ^[2]. The co-expression levels of TNFRSF13B and APRIL in the synovial tissue of rheumatoid arthritis patients positively correlate with the degree of inflammation, suggesting a key role for the TACI-APRIL axis in the persistence of chronic inflammation ^[2].

In normal immune processes, TACI activation promotes B cell maturation and antibody production. When TNFRSF13B mutations occur (e.g., A181E), its ligand-binding capacity decreases, leading to impaired B cell activation, reduced immunoglobulin production, and consequently causing Common Variable Immunodeficiency Disease (CVID). Furthermore, rare pathogenic variants of TNFRSF13B have been detected in MIS-C patients; these variants disrupt immune homeostasis and exacerbate inflammatory responses ^[8].

2.2 Tumor Regulatory Mechanism

In tumors, TNFRSF13B can exert effects by regulating cell survival, proliferation, and the tumor immune microenvironment. During the transformation of Chronic Lymphocytic Leukemia (CLL) to Richter Syndrome (RS), TNFRSF13B expression is upregulated. Binding with APRIL and BAFF in the tumor microenvironment activates the NF-κB pathway, promoting tumor cell proliferation ^[6]. In melanoma, its high expression promotes Regulatory T cell (Treg) enrichment and enhances immunosuppressive function via the JAK-STAT pathway, inhibiting effector T cell activity, thereby facilitating tumor immune escape ^[7]. Additionally, in breast cancer, TNFRSF13B expression is negatively correlated with mammographic density and cancer risk ^[3,5].

4. TNFRSF13B (TACI) Related Diseases

4.1 Hematologic Diseases

4.1.1 Chronic Lymphocytic Leukemia (CLL) and Richter Syndrome (RS)

CLL is a common mature B-cell malignancy, with approximately 2-10% of patients eventually progressing to RS. Studies show that TNFRSF13B expression is significantly upregulated in tumor cells of RS patients, and its level positively correlates with NF-κB pathway activity [6]. TACI binds to APRIL and BAFF secreted by monocytes, promoting tumor cell survival and inflammatory factor release, thereby accelerating the transformation of CLL to RS ^[6]. Moreover, patients with high TNFRSF13B expression have a poorer prognosis and significantly shorter survival, suggesting its potential as a biomarker.

4.1.2 Multisystem Inflammatory Syndrome in Children (MIS-C)

MIS-C is a severe inflammatory reaction syndrome following SARS-CoV-2 infection. Approximately 6.7% of patients harbor TNFRSF13B pathogenic variants, primarily frameshift mutations (e.g., c.20-idup) ^[8]. These variants impair TACI structure and signal transduction function, disrupting B cell regulation and thereby triggering abnormal inflammatory responses and multi-organ damage. Patients carrying these mutations are more prone to shock and cardiac dysfunction, indicating that TNFRSF13B is an important molecular marker affecting disease severity ^[8].

4.2 Autoimmune Diseases

4.2.1 Lupus Nephritis (LN)

LN is a severe complication of Systemic Lupus Erythematosus. Studies show that TNFRSF13B mRNA can be detected in patient urinary sediment, and its expression frequency correlates with LN type and disease activity ^[4]. The detection rate is significantly higher in Type III/IV LN compared to Type V (42.85% vs. 0%). Activation of the TACI-BAFF/APRIL axis triggers the NF-κB pathway, inducing the expression of inflammatory factors IL-6, TNF-α, and chemokine CCL21, promoting immune cell infiltration and immune complex deposition ^[4]. Furthermore, urinary TACI expression levels closely correlate with the SLEDAI-2K index and complement C4 levels, suggesting its potential value as a non-invasive biomarker for LN ^[4].

4.3 Malignant Tumors

4.3.1 Melanoma

Melanoma is the most aggressive skin cancer. TNFRSF13B is highly expressed in melanoma tissue and is closely associated with lymph node metastasis ^[7]. TACI can upregulate FOXP3 expression via the JAK-STAT pathway, promoting Treg proliferation and enhancing the immunosuppressive environment ^[7]. Simultaneously, it synergizes with immunosuppressive molecules like LAG3 and NT5E, further weakening anti-tumor immune responses. Patients with high TNFRSF13B expression have significantly shorter overall survival and progression-free survival ^[7].

4.3.2 Breast Cancer

Research indicates that TNFRSF13B expression is negatively correlated with mammographic density, and increased BMI is significantly associated with decreased gene expression (an 8.5% decrease per 10 kg/m² increase) ^[3,5]. Since mammographic density is an independent risk factor for breast cancer, TNFRSF13B may influence cancer risk by regulating the proliferation and differentiation of mammary epithelial cells ^[5]. Additionally, its interaction with molecules such as ESR1 and RANK may affect the estrogen pathway and breast tissue homeostasis, further increasing the probability of tumorigenesis.

4.4 Immunodeficiency Diseases

Common Variable Immunodeficiency Disease (CVID) is a primary immunodeficiency characterized by B cell functional defects and antibody production impairment. Approximately 10%-20% of CVID patients carry TNFRSF13B pathogenic mutations (e.g., A181E, C104R), which weaken TACI's binding capacity to BAFF/APRIL ^[1]. Functionally, these mutations inhibit B cell activation, immunoglobulin class switching, and plasma cell generation, leading to recurrent infections and autoimmune complications in patients. Patients with mutations are more likely to develop severe diseases such as chronic lung disease and lymphoma ^[1].