Blocking Tumor Necrosis Factor Paved the Way for Targeted Therapeutics in Inflammatory Diseases

If you or someone you know lives with rheumatoid arthritis (RA), Crohn’s disease (CD), or ankylosing spondylitis (AS), you’ve likely heard of tumor necrosis factor inhibitors (TNFi)—medications that have transformed how we treat these painful, disabling inflammatory conditions. But the story of TNFi starts with a molecule called tumor necrosis factor (TNF), a cytokine that evolved from a cancer research curiosity to a cornerstone of modern inflammation therapy.

The Discovery of TNF: From Cancer Research to Inflammation

In 1975, cancer researcher Lloyd Old and his team were searching for substances that could shrink tumors. They found a protein in the blood of mice treated with endotoxin (a bacterial toxin) and BCG (a tuberculosis vaccine) that caused tumors to die. They named it tumor necrosis factor (TNF). Later, scientists realized TNF was identical to cachectin—a molecule responsible for the severe weight loss (cachexia) seen in people with advanced cancer.

Once TNF was purified, researchers made a critical observation: TNF is a potent inflammatory cytokine—a chemical messenger that triggers swelling, pain, and tissue damage. Its tumor-killing effect? Indirect. TNF ramps up inflammation, which cuts off blood flow to tumors, causing them to die. But using TNF to treat cancer directly was disappointing. However, blocking TNF yielded a surprise: it reduced side effects of cancer immunotherapy (like immune checkpoint inhibitors) and may enhance their effectiveness when combined—a strategy now being explored for cancer care.

The Great Name Confusion: TNF vs. TNF-α

For a short time, TNF was called TNF-α because another molecule, lymphotoxin (LT), was named TNF-β. But scientists pushed back: TNF and LT share just 28% similarity at the protein level, making the names misleading. In 1993, a new member of the LT family (LTβ) was discovered, and “TNF-β” was abandoned. Today, major biology databases—the HUGO Gene Nomenclature Committee and UniProt—use “TNF” exclusively. Yet “TNF-α” still appears in some papers; authors are urged to stick with “TNF” to avoid confusion.

TNF Inhibitors: From Sepsis Failure to Inflammation Success

TNFi are the first cytokines successfully targeted for inflammatory diseases. The first two TNFi—infliximab (a monoclonal antibody) and etanercept (a fusion protein of TNF receptor and IgG1)—were initially tested for sepsis (a life-threatening infection response). But blocking TNF didn’t help sepsis patients. The breakthrough came when researchers noticed TNF was overexpressed in the joints of RA patients and the gut of CD patients.

Testing TNFi in these conditions was transformative:

Rheumatoid Arthritis (RA): Five TNFi (infliximab, golimumab, adalimumab, certolizumab pegol, etanercept) and their biosimilars are now standard. They work exceptionally well—both in clinical trials and real-world care—and are the gold standard for RA treatment.
Inflammatory Bowel Disease (IBD): TNFi reduce symptoms, improve quality of life, and cut down on surgery for CD and ulcerative colitis. They even treat extra-intestinal issues, like joint pain linked to IBD.

How TNFi Work—And Why They’re Not All the Same

TNFi fall into two categories:

Monoclonal antibodies (e.g., infliximab, adalimumab): These bind to soluble TNF (floating in blood) and transmembrane TNF (on cell surfaces).
Fusion proteins (e.g., etanercept): A mix of TNF receptor and IgG1 that neutralizes TNF and blocks LTα/LTβ (other inflammatory molecules).

Key differences:

Etanercept doesn’t work for IBD or non-infectious uveitis, unlike antibody-based TNFi.
Antibodies can trigger immune cells to kill TNF-producing cells (via antibody-dependent cellular cytotoxicity, ADCC) or activate complement (a protein system that destroys cells).
“Reverse signaling” through transmembrane TNF may also kill cells that make TNF.

These subtle differences matter: It’s common for a patient to fail one TNFi but respond to another.

TNF in Ankylosing Spondylitis (AS) and Spondyloarthritis (SpA)

TNF is overexpressed in the sacroiliac joints (where the spine meets the pelvis) of AS patients—a type of SpA that causes spine inflammation and fusion. Inspired by RA/CD success, researchers tested infliximab in SpA patients in 2000. Within two weeks, patients reported less pain, and inflammation markers (like C-reactive protein) dropped sharply. The effect was as strong as in RA.

Today, TNFi are disease-modifying therapies for AS/SpA:

They relieve symptoms (pain, stiffness) and improve function.
Long-term use (over 4 years) slows spine damage—like new bone growth (neo-ossification)—a critical benefit for preventing disability.
Real-world studies confirm TNFi reduce heart risks and disability in SpA patients, just like in RA.

TNF: The Benchmark for Targeted Therapy

TNFi set the bar for developing new treatments. For example:

Blocking interleukin-17 (IL-17) didn’t work as well as TNFi for RA, so it was considered a “failure.” But IL-17 inhibitors (IL-17i) are exceptional for psoriasis and SpA. Drugs like secukinumab (blocks IL-17A) or bimekizumab (blocks IL-17A/IL-17F) work as well as TNFi for SpA—even in patients who didn’t respond to TNFi.
We don’t know if TNFi or IL-17i are “better” (no head-to-head trials), but switching between them is effective. Scientists are also curious: Could combining TNFi and IL-17i yield synergistic benefits?

TNFi are the gold standard for testing new therapies. If a drug doesn’t perform as well as TNFi, it’s unlikely to gain approval. They also help us understand how cytokines drive disease—paving the way for even more precise treatments.

The Bottom Line

Blocking TNF changed everything. It turned inflammatory diseases from lifelong, disabling conditions into manageable ones. For millions of people with RA, IBD, or SpA, TNFi aren’t just drugs—they’re a second chance at a normal life. And as we learn more about TNF and other cytokines, we’re moving closer to therapies that are even more targeted, effective, and safe.

Cong-Qiu Chu
Division of Arthritis and Rheumatic Diseases, Oregon Health & Science University and Rheumatology Section, VA Portland Health Care System, Portland, OR 97239, USA

doi.org/10.1097/CM9.0000000000001846

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