CD40LG: A Key Molecule in Immune Regulation, Disease Associations and Therapeutic Progress

2. Mechanism of Action and Signaling Pathways of CD40LG

4. Progress in Drug Research on the CD40-CD40LG Axis

1. Introduction

CD40LG (also known as CD154) is a key co-stimulatory molecule in the immune system and belongs to the tumor necrosis factor (TNF) superfamily. It usually binds to CD40 in trimeric form and plays an important role in T cell-dependent B cell activation, antibody class switching, and immune memory formation ^[1]. Early studies mainly focused on its expression in activated CD4+ T cells, but subsequent studies have shown that CD40LG can also be found in various cells such as platelets, B cells, endothelial cells, and macrophages, among which platelets are the main source of circulating soluble CD40LG ^[1,2].

The CD40LG-CD40 axis is not only involved in normal immune responses, but also closely associated with various diseases. CD40LG functional deficiency can cause X-linked hyper-IgM syndrome (XHIGM), leading to antibody class switching disorders and increased susceptibility to infection ^[3,4]; abnormal activation of this pathway is also involved in autoimmunity, inflammatory responses, atherosclerosis, and tumor immune regulation ^[1,18,21]. In addition, the role of CD40LG has obvious cell type and disease context dependence, and can exhibit pro-inflammatory, immune-supporting or immunosuppressive effects in different microenvironments ^[6,7]. Therefore, systematically sorting out the molecular characteristics, signaling mechanisms, disease associations, and drug research progress of CD40LG is of great significance for understanding its biological functions and clinical translational value.

2. Mechanism of Action and Signaling Pathways of CD40LG

2.1 Classic Signaling Pathways: NF-κB and JAK-STAT

After CD40-CD40LG binding, multiple classic downstream pathways can be activated, among which the most important are NF-κB and JAK-STAT. This signaling axis can be involved in cell proliferation, differentiation, cytokine production, and apoptosis regulation. Studies have shown that CD40 can inhibit hepatitis B virus replication and transcription by activating the JAK-STAT pathway, and further regulate the expression of interferon-stimulated genes such as BST2, suggesting that it plays an important role in antiviral immunity ^[8]. In addition, NF-κB and apoptosis-related signals are also closely related to CD40LG; in the study of pneumonia treatment mechanisms, CD40LG has been identified as a key target in the NF-κB and apoptosis pathways ^[9].

2.2 miRNA Regulation: Affecting Inflammation, Angiogenesis and Leukemia Signaling Responses

In addition to classic protein signaling, miRNAs are also an important level regulating the CD40/CD40LG axis. Studies have found that miR-424 and miR-503 can directly target the 3'UTR of CD40 and inhibit its expression in endothelial cells ^[10]. Under pro-inflammatory stimulation, these two miRNAs are downregulated, leading to increased CD40 expression, thereby promoting inflammation-related angiogenesis. Furthermore, miR-424 and miR-503 are directly regulated by PPARγ, forming a PPARγ-dependent miR-424/503-CD40 axis ^[10].

In chronic lymphocytic leukemia, the miR-29 family is also involved in CD40 signaling regulation. Downregulation of miR-29a, miR-29b, and miR-29c can enhance the response of CLL cells to CD40 activation and its downstream NF-κB signaling by directly targeting TRAF4 ^[11]. Meanwhile, BCR signaling can inhibit miR-29 expression through MYC, thereby enhancing CD40-NF-κB signaling, and this regulatory process can be intervened by BCR inhibitors such as ibrutinib and idelalisib ^[11].

2.3 lncRNA and ceRNA Mechanism: Expanding the CD40 Regulatory Network

Long non-coding RNAs are also involved in the regulation of the CD40 axis. For example, lncRNA MSTRG.22719.16 can interact with ocu-miR-326-5p through the ceRNA mechanism, thereby regulating CD40 expression. In local thrombosis induced by PMMA bone cement, activation of the MSTRG.22719.16/ocu-miR-326-5p/CD40 axis can reduce thrombosis, suggesting its potential intervention value ^[12]. Overall, the CD40-miRNA axis is of great significance in cell fate determination and pathological state regulation ^[13], but its systematic mechanism still needs further study.

3. CD40LG-Related Diseases

Abnormal CD40LG function is associated with a variety of diseases, including primary immunodeficiency, autoimmune and inflammatory diseases, and tumors. In different diseases, the direction and intensity of action of this molecule are significantly affected by cell origin and microenvironment.

3.1 X-linked Hyper-IgM Syndrome (XHIGM)

XHIGM is the most typical disease type caused by CD40LG deficiency. Patients often present with recurrent infections, including common bacteria as well as opportunistic infections or viral infections such as Pneumocystis jirovecii, Cryptosporidium, Talaromyces marneffei, cytomegalovirus, and adenovirus ^[3,14,15]. The respiratory tract and biliary system are commonly involved sites, and some patients may also present with interstitial pneumonia or pulmonary alveolar proteinosis as the initial manifestation ^[16,17]. In addition, patients may be accompanied by autoimmune and inflammatory complications, increasing prognostic risk ^[18].

The type of CD40LG gene mutation is closely related to clinical phenotype. Some missense mutations can retain CD40L expression but weaken its binding ability to CD40, forming a relatively mild or atypical phenotype ^[4]; while truncating mutations usually indicate more severe functional defects ^[17]. Diagnostically, XHIGM cannot rely solely on immunoglobulin profiles, because some patients may present with atypical serological characteristics. Combining genetic testing, flow cytometry, and CD40 binding function analysis can more accurately identify such patients ^[4,15].

3.2 Autoimmune and Inflammatory Diseases

In rheumatoid arthritis, CD40LG is considered to have potential biomarker value. Studies have shown that the level of CD40LG antibody in the serum of RA patients is elevated, especially in patients with interstitial lung disease or severe bone destruction, suggesting that it may be related to disease activity and complication risk ^[19]. In systemic lupus erythematosus, abnormal activation of the CD40LG-CD40 axis can promote B cell activation and autoantibody production, which is one of the important pathogenic mechanisms ^[20]. Blocking strategies targeting this pathway have shown potential in alleviating lupus nephritis and overall autoimmune symptoms in animal models ^[20].

In acute liver injury, the IFNγ-CD40 axis is closely related to intrahepatic microcirculation disorders. IFNγ can upregulate CD40 expression in endothelial cells, promote its interaction with CD40LG, induce tissue factor expression and aggravate coagulation and liver injury ^[21]. In atherosclerosis, the role of CD40LG shows cell origin differences: T cell-derived CD40L has a greater impact on plaque formation and stability, while platelet-derived CD40L is more important for thrombosis ^[1]. In addition, the CD40/CD40LG axis also plays an important regulatory role in HBV clearance, local thrombosis, and allergen tolerance ^[6,8,12].

3.3 Tumorigenesis and Progression

The role of CD40LG in tumors is dual. Taking breast cancer as an example, low expression in tumor tissue is associated with more advanced stage and worse prognosis, and is significantly associated with infiltration of various immune cells, suggesting that it may be involved in shaping the tumor immune microenvironment ^[21]. In pan-cancer analysis, CD40LG has also been identified as a T cell priming marker, and its expression is positively correlated with immunotherapy-related features such as MSI-H, high TMB, and high PD-L1 expression ^[22].

In specific tumors, CD40LG is also involved in disease progression mechanisms. For example, in T-ALL, BACH2 can affect tumor cell survival and proliferation by inhibiting CD28 and CD40LG expression ^[23]; in Waldenström macroglobulinemia, the CD40/CD40L axis can support a Treg-mediated immunosuppressive microenvironment ^[7]; in some studies on T-cell lymphoma and oral squamous cell carcinoma, CD40LG has also been suggested to be involved in tumor maintenance or drug response ^[24-26].

4. Progress in Drug Research on the CD40-CD40LG Axis

Drug development surrounding the CD40-CD40LG axis is mainly divided into two categories: one is to inhibit this pathway, used in autoimmune diseases, transplant rejection and other scenarios; the other is to activate this pathway to enhance anti-tumor immunity.

Currently, significant progress has been made in the development of drugs targeting CD40LG. A variety of drug types (including fusion proteins, monoclonal antibodies, oncolytic viruses, small molecule drugs, and therapeutic vaccines) have entered clinical studies for indications such as autoimmune diseases, transplant rejection, and various malignancies, with some candidates having advanced to Phase 3 clinical trials. The table below summarizes the representative pipeline programs.

Drug Name	Target	Drug Type	Indications	Research Institutions	Highest Development Phase
Dazodalibep	CD40L	Fusion Protein	Sjögren's Syndrome; Lupus Nephritis; Focal Segmental Glomerulosclerosis	Amgen, Inc.; The Ohio State University Wexner Medical Center; Horizon Therapeutics Ltd. (Ireland)	Phase 3
Dapirolizumab pegol	CD40L	Monoclonal Antibody	Systemic Lupus Erythematosus	Biogen, Inc.; UCB Biopharma SRL; UCB Trading (Shanghai) Co., Ltd.; UCB SA	Phase 3
Frexalimab	CD40L	Monoclonal Antibody	Multiple Sclerosis; Secondary Progressive Multiple Sclerosis; Relapsing-Remitting Multiple Sclerosis; Kidney Transplant Rejection, etc.	Sanofi; Sanofi-Aventis Recherche & Développement SA; ImmuNext, Inc.	Phase 3
Tegoprubart	CD40L	Monoclonal Antibody	IgA Nephropathy; Kidney Transplant Rejection; Amyotrophic Lateral Sclerosis; Heart Transplant Rejection	ALS Therapy Development Foundation, Inc.; Eledon Pharmaceuticals, Inc.	Phase 2
Delolimogene mupadenorepvec	4-1BBL x CD40L	Oncolytic Virus	Bile Duct Cancer; Pancreatic Ductal Adenocarcinoma	Uppsala University Hospital; Lokon Pharma AB	Phase 2
OPT-101	CD40L	Small Molecule Drug	Community-Acquired Pneumonia; Sepsis	OP LLC	Phase 2
TriMixDC	CD40L x CD70 x TLR4	Therapeutic Vaccine; Dendritic Cell Vaccine; Melanoma	Melanoma	-	Phase 2
TNX-1500	CD40L	Monoclonal Antibody	Immunosuppression; Kidney Transplant Rejection; Autoimmune Diseases; Organ Transplant Rejection	Tonix Pharmaceuticals Holding Corp.; Tonix Pharmaceuticals, Inc.	Phase 2
Bria-OTS	CD40L x CD80 x CD86 x CSF-3R x Type I IFN Receptor x IL-12R x IL-7Rα	Therapeutic Vaccine	Recurrent Breast Cancer; Breast Cancer	BriaCell Therapeutics Corp.	Phase 1/2
Adze1.C (Adze Biotechnology)	CD40L	Oncolytic Virus	Melanoma; Metastatic Melanoma; Bladder Cancer; Glioblastoma; Liver Cancer; Triple-Negative Breast Cancer	Adze Biotechnology, Inc.; Adze Biotechnology Australia Pty Ltd	Phase 1
RP-3	4-1BB x CD40L x CTLA4	Oncolytic Virus	Advanced Malignant Solid Tumors	Replimune, Inc.	Phase 1
MEM-288	CD40L x IFNβ	Oncolytic Virus	Advanced Cancers; BRAF V600E Positive Melanoma; Brain Metastasis; Cutaneous Squamous Cell Carcinoma, etc.	Memgen, Inc.	Phase 1
Tumor-infiltrating Lymphocytes (H. Lee Moffitt Cancer Center and Research Institute)	CD40L	Tumor-Infiltrating Lymphocytes	Non-Muscle Invasive Bladder Cancer; Bladder Urothelial Carcinoma; Advanced Non-Small Cell Lung Cancer, etc.	H. Lee Moffitt Cancer Center & Research Institute, Inc.	Phase 1
Lu-AG22515	CD40L x albumin	Bispecific Antibody	Graves' Ophthalmopathy; Autoimmune Diseases	H. Lundbeck A/S; Aprilbio Co. Ltd.	Phase 1
Valo D102	CD40L x OX40L	Recombinant Vector Vaccine; Therapeutic Vaccine; Oncolytic Virus	Melanoma; Non-Small Cell Lung Cancer; Sarcoma; Colorectal Cancer; Cutaneous Melanoma, etc.	Valo Therapeutics Oy	Phase 1
IBI-355	CD40L	Monoclonal Antibody	Primary Sjögren's Syndrome; Systemic Lupus Erythematosus	Innovent Biologics (Suzhou) Co., Ltd.	Phase 1

(Data as of March 19, 2026, sourced from Synapse)

5. CD40LG Research Tools

CD40LG is a key molecule in adaptive immune regulation that plays a central role in B cell activation, antibody class switching, and immune memory formation. Its dysfunction is closely associated with XHIGM, autoimmune diseases, inflammatory diseases, and tumors ^{[3, 18, 21]}. Meanwhile, CD40LG has dual potential as both a disease marker and a therapeutic target, and its value in precision medicine is receiving increasing attention. CUSABIO provides CD40LG recombinant proteins, antibodies, and ELISA kits to support your research on related mechanisms and targeted drug development.

● CD40LG Recombinant Proteins

Recombinant Human CD40 ligand (CD40LG), partial (Active); CSB-MP004937HU3

Recombinant Mouse CD40 ligand (Cd40lg), partial (Active); CSB-MP004937MO1

● CD40LG Antibodies

CD40LG Antibody

CSB-PA06005A0Rb

CD40LG Antibody

CSB-PA004937GA01HU

● CD40LG ELISA Kits

Human Soluble Cluster of differentiation 40 ligand,sCD40L ELISA Kit

CSB-E04716h

Rat Soluble Cluster of differentiation 40 ligand,sCD40L ELISA Kit

CSB-E07395r

Mouse Soluble Cluster of differentiation 40 ligand,sCD40L ELISA Kit

CSB-E04717m

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