Tumor Necrosis Factor-α (TNFα) is a key cytokine involved in various inflammatory diseases and macrophage biology. Discovered over 20 years ago, TNFα signals through two receptors, TNFR1 and TNFR2, regulating cell proliferation, survival, differentiation, and apoptosis. Macrophages are major producers and responders to TNFα, and its dysregulated production is linked to diseases like rheumatoid arthritis, Crohn's disease, atherosclerosis, and sepsis. TNFα orchestrates cytokine cascades and is a therapeutic target for inflammatory diseases, with anti-TNFα drugs now used to treat conditions such as rheumatoid arthritis and inflammatory bowel disease. TNFα is synthesized as a 27-kDa precursor, cleaved to a 17-kDa soluble form. It binds to TNFR1 and TNFR2, triggering signaling pathways that regulate NF-κB, MAPK, and other pathways, leading to inflammation, cell survival, and apoptosis. TNFR1 is constitutively expressed, while TNFR2 is regulated and involved in immune responses. TNFα signaling in macrophages is crucial for inflammation, tissue repair, and disease pathogenesis. It also influences macrophage proliferation, apoptosis, differentiation, and atherosclerosis. TNFα plays a role in osteoclastogenesis and bone remodeling, and its inhibition can reduce bone destruction in diseases like rheumatoid arthritis. Anti-TNFα therapies, including monoclonal antibodies and fusion proteins, are effective in treating inflammatory diseases. However, challenges remain in targeting specific cells and tissues, prompting research into gene therapy and RNA-based approaches for more targeted treatment. Understanding TNFα signaling mechanisms is essential for developing better therapies for inflammatory and autoimmune diseases.Tumor Necrosis Factor-α (TNFα) is a key cytokine involved in various inflammatory diseases and macrophage biology. Discovered over 20 years ago, TNFα signals through two receptors, TNFR1 and TNFR2, regulating cell proliferation, survival, differentiation, and apoptosis. Macrophages are major producers and responders to TNFα, and its dysregulated production is linked to diseases like rheumatoid arthritis, Crohn's disease, atherosclerosis, and sepsis. TNFα orchestrates cytokine cascades and is a therapeutic target for inflammatory diseases, with anti-TNFα drugs now used to treat conditions such as rheumatoid arthritis and inflammatory bowel disease. TNFα is synthesized as a 27-kDa precursor, cleaved to a 17-kDa soluble form. It binds to TNFR1 and TNFR2, triggering signaling pathways that regulate NF-κB, MAPK, and other pathways, leading to inflammation, cell survival, and apoptosis. TNFR1 is constitutively expressed, while TNFR2 is regulated and involved in immune responses. TNFα signaling in macrophages is crucial for inflammation, tissue repair, and disease pathogenesis. It also influences macrophage proliferation, apoptosis, differentiation, and atherosclerosis. TNFα plays a role in osteoclastogenesis and bone remodeling, and its inhibition can reduce bone destruction in diseases like rheumatoid arthritis. Anti-TNFα therapies, including monoclonal antibodies and fusion proteins, are effective in treating inflammatory diseases. However, challenges remain in targeting specific cells and tissues, prompting research into gene therapy and RNA-based approaches for more targeted treatment. Understanding TNFα signaling mechanisms is essential for developing better therapies for inflammatory and autoimmune diseases.