TLR4

Toll-like receptor 4 (TLR4), also known as CD284 or hToll, is a transmembrane pattern recognition receptor critical for innate immune responses. It primarily recognizes bacterial lipopolysaccharide (LPS) in complex with myeloid differentiation factor 2 (MD-2) and CD14, triggering MyD88-dependent and TRIF-dependent signaling pathways. These pathways activate NF-κB and MAPK cascades, inducing proinflammatory cytokines and type I interferons. TLR4 dysregulation is implicated in sepsis, rheumatoid arthritis, neuroinflammatory disorders, and cancers such as breast and colorectal carcinomas. Drug development has focused on TLR4 antagonists like Eritoran (E5564), a synthetic lipid A analog that failed Phase III trials for sepsis, and TAK-242, a small-molecule inhibitor targeting TLR4 intracellular signaling that showed limited efficacy in clinical studies.
Despite therapeutic challenges, TLR4 modulation remains a promising strategy due to its dual role in inflammation and tumor microenvironment regulation. Recent studies highlight its involvement in non-infectious diseases, including atherosclerosis, obesity-induced insulin resistance, and Alzheimer’s disease via neuroinflammatory pathways. Novel approaches include repurposing the vasodilator Ibudilast for neuroprotection and developing TLR4/MD-2 interface inhibitors like NI-0101, a monoclonal antibody that attenuated cytokine release in autoimmune models. Nanocarrier-based TLR4 agonists, such as CRX-527, are being explored as vaccine adjuvants to enhance antitumor immunity. Combination therapies with checkpoint inhibitors (e.g., anti-PD-1) demonstrate synergistic effects in preclinical cancer models, underscoring TLR4's potential as a multifaceted therapeutic target.