TNF and TNFSF: Advances in Autoimmune and Inflammatory Disease Therapies

TNF and TNFSF: Tumor necrosis factor (TNF) and its superfamily (TNFSF) play central roles in immune regulation, inflammation, and cell death. Since their discovery, TNF-targeted therapies have become key treatments for autoimmune and inflammatory diseases. Advances in biotechnology have led to the development of FDA-approved TNF inhibitors and TNFSF-based biologics, including monoclonal antibodies, fusion proteins, and CAR-T cell therapies. These agents have transformed clinical outcomes for conditions such as rheumatoid arthritis, lupus, and multiple myeloma. Continued exploration of TNFSF signaling and molecular pathways offers new opportunities for precision medicine and next-generation immunotherapeutics.

Introduction

As early as the 18th century, physicians observed that tumors in some cancer patients occasionally regressed following severe bacterial infections. They hypothesized that a biological factor might be responsible for this tumor necrosis activity. However, due to the limitations of medical science at the time, the identity of this factor remained unknown. It was not until 1975 that E.A. Carswell and colleagues discovered that mice previously vaccinated with BCG and later injected with bacterial lipopolysaccharide developed a serum substance capable of inducing hemorrhagic necrosis in various tumors. This substance was named tumor necrosis factor (TNF).

Subsequent research revealed two main forms: TNF-α, produced primarily by macrophages, and TNF-β, or lymphotoxin (LT), secreted by T lymphocytes. Today, the term “TNF” typically refers to TNF-α.

Modern studies have shown that the human tumor necrosis factor superfamily (TNFSF) consists of 18 genes that encode over 20 protein products (including heterodimers). These ligands interact with 29 members of the TNF receptor superfamily (TNFRSF), collectively activating a range of overlapping and distinct signaling pathways. At least 40 ligand–receptor interactions have been experimentally confirmed, with more predicted. TNFSF molecules are essential for the development and coordination of both the innate and adaptive immune systems. However, when their regulation is disrupted, they can drive inflammatory and autoimmune diseases by promoting excessive activation of antigen-presenting cells, T cells, and B cells, as well as overproduction of TNFSF proteins—ultimately leading to pathological damage in tissues.

FDA-Approved TNF Inhibitors

Etanercept – A fusion protein composed of the soluble portion of the tumor necrosis factor receptor (TNFR) linked to the Fc fragment of human IgG1. It functions by binding to TNF and preventing its interaction with cell surface receptors, thereby reducing inflammation. Etanercept is widely used to treat rheumatoid arthritis and other inflammatory diseases. It received FDA approval in 1998.

Certolizumab – A tumor necrosis factor (TNF) inhibitor indicated for the treatment of multiple autoimmune and autoinflammatory disorders, including Crohn’s disease, rheumatoid arthritis, active psoriatic arthritis, ankylosing spondylitis, axial spondyloarthritis, and plaque psoriasis. It was first approved by the FDA in 2008, with an updated indication added on March 28, 2019.

Infliximab – A chimeric monoclonal antibody derived from both human and mouse components that targets TNF-α, preventing its binding to TNFR1 and TNFR2. Infliximab is used to treat Crohn’s disease and rheumatoid arthritis and was the first TNF inhibitor approved by the FDA in 1998. Its introduction marked a significant milestone in biologic therapy for chronic inflammatory diseases.

Golimumab – A humanized IgG1κ monoclonal antibody that neutralizes TNF-α with high potency. It exhibits anti-inflammatory and anti-tumor activities by inhibiting cytokines such as IL-6 and IL-1β, and can induce apoptosis in specific immune cells. Golimumab is used to prevent inflammation and protect cartilage and bone from damage and is indicated for rheumatoid arthritis and cancer research. The FDA approved Golimumab in 2009.

Ozoralizumab – A novel humanized anti-TNFα antibody designed to bind human serum albumin, extending its half-life and improving pharmacokinetic properties. It represents a new generation of TNF inhibitors and is primarily indicated for rheumatoid arthritis research. Approved in Japan in 2022, Ozoralizumab offers a promising therapeutic alternative with enhanced molecular stability.

Adalimumab – A fully human recombinant IgG1 monoclonal antibody that specifically binds to TNF-α, blocking its interaction with p55 and p75 cell surface receptors. Adalimumab is approved for the treatment of rheumatoid arthritis, ankylosing spondylitis, psoriasis, and several other chronic inflammatory diseases. It was approved by the FDA in 2002 and remains one of the most widely used biologic agents in TNF-targeted therapy.

FDA-Approved TNFSF-Based Therapies

Denosumab – A fully human monoclonal antibody that binds to and inhibits the RANKL (Receptor Activator of Nuclear Factor κB Ligand), thereby suppressing osteoclast activity and reducing bone resorption. Denosumab exhibits anticancer and bone-protective effects, significantly lowering the risk of hip, vertebral, and non-vertebral fractures. It was first approved by the FDA in June 2010 and is widely used in the management of osteoporosis and cancer-related bone loss.

Belimumab – A human IgG1λ monoclonal antibody that specifically targets and inhibits B-cell activating factor (BAFF, also known as BLyS). By blocking BAFF, Belimumab reduces abnormal B-cell activation and autoantibody production. It is approved for the treatment of systemic lupus erythematosus (SLE) and lupus nephritis, and has also been studied for its effects on fatigue and immune modulation. The FDA granted approval in March 2011.

Brentuximab Vedotin – A chimeric monoclonal antibody directed against CD30, conjugated with a cytotoxic agent to enhance antitumor efficacy. It is indicated for relapsed or refractory Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma. Brentuximab was first approved by the FDA in August 2011, representing a major advance in targeted antibody-drug conjugate therapy.

Tisagenlecleucel – An autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy designed to recognize and eliminate CD19-expressing B cells. It is primarily used to treat refractory or relapsed diffuse large B-cell lymphoma and acute lymphoblastic leukemia. Tisagenlecleucel marked a breakthrough as one of the first CAR-T therapies approved by the FDA.

Belantamab Mafodotin – Derived from Belantamab, a humanized IgG1 monoclonal antibody targeting BCMA (B-cell maturation antigen, TNFRSF17), this therapy is conjugated to a cytotoxic agent to enhance tumor cell killing. It was approved by the FDA in August 2020 for the treatment of relapsed or refractory multiple myeloma, following the initial FDA approval of Belantamab in August 2017.

Idecabtagene Vicleucel (bb2121) – A CAR-T cell therapy engineered to target BCMA for the treatment of relapsed or refractory multiple myeloma. It harnesses the patient’s own immune cells to selectively destroy malignant plasma cells. The FDA approved Idecabtagene Vicleucel on March 26, 2021.

Teclistamab – A bispecific antibody that simultaneously binds BCMA on myeloma cells and CD3 on T cells. This dual targeting activates T cells to attack and lyse myeloma cells through T-cell–mediated cytotoxicity. Teclistamab is indicated for research and treatment of multiple myeloma and related hematologic malignancies.

Ciltacabtagene Autoleucel – A genetically modified autologous CAR-T cell immunotherapy targeting BCMA, designed to recognize and destroy myeloma cells. It received accelerated FDA approval on October 25, 2022, following its initial approval in February 2022 for patients with relapsed or refractory multiple myeloma who had previously undergone multiple lines of therapy.

Elranatamab – A bispecific antibody engineered to target both BCMA on myeloma cells and CD3 on T cells. By bridging these targets, Elranatamab effectively redirects T cells to attack and eliminate myeloma cells, inducing potent cytotoxic immune responses. It is primarily indicated for the treatment of relapsed or refractory multiple myeloma and received accelerated FDA approval on August 14, 2023.

Autoimmune Diseases and Advances in Anti-Inflammatory Therapies

Autoimmune diseases arise when certain triggers cause the immune system to lose its ability to distinguish between self and non-self, leading it to mistakenly attack and destroy the body’s own healthy tissues. Commonly affected areas include the blood vessels, connective tissues, joints, and skin.

During the 19th and 20th centuries, the advancement of chemical research led to the development of nonsteroidal anti-inflammatory drugs (NSAIDs), which proved highly effective in managing inflammation. However, despite their therapeutic benefits, NSAIDs are often associated with significant adverse effects, such as gastrointestinal bleeding, ulcer formation, and kidney damage.

Among the key mediators of inflammation, tumor necrosis factor-α (TNF-α) is recognized as a major pro-inflammatory cytokine that plays a pivotal role in the development and progression of autoimmune and inflammatory diseases. Consequently, anti-TNF therapies have become a cornerstone in the treatment of many autoimmune disorders.

With rapid progress in molecular biology and immunology, researchers have identified numerous signaling pathways and associated proteins involved in autoimmune pathogenesis. These discoveries have expanded the pool of potential therapeutic targets beyond TNF-α. For instance, small-molecule inhibitors and macrocyclic compounds that target the immunoproteasome, nuclear export proteins, NF-κB, and TNF-α itself have demonstrated strong immunomodulatory effects. Such compounds hold great promise for the development of next-generation treatments for autoimmune and chronic inflammatory diseases.

Conclusion

The discovery of tumor necrosis factor (TNF) and its superfamily has revolutionized our understanding of inflammation, immunity, and autoimmune disease mechanisms. From early observations of tumor regression to the development of sophisticated biologics and CAR-T cell therapies, TNF and TNFSF-targeted treatments have transformed modern medicine. FDA-approved inhibitors and antibody-based therapeutics continue to provide effective options for managing autoimmune and malignant conditions, improving patient outcomes and quality of life. Ongoing research into signaling pathways, immune regulation, and next-generation small-molecule modulators promises even greater therapeutic precision. As our molecular insights deepen, TNF and TNFSF will remain at the forefront of innovations in immunotherapy and the treatment of chronic inflammatory diseases.