Zhiling He

Lidocaine, an amide-type regional anesthetic, has been an important medication in the field of anesthesia since its clinical approval. Recently, lidocaine has emerged as a powerful immunomodulatory agent beyond its classical anesthetic properties. This review has summarized the recent basic and clinical studies with sufficient evidence on the multifaceted effects of lidocaine on both innate and adaptive immune cells, including macrophages, neutrophils, eosinophils, basophils, natural killer (NK) cells, mast cells, dendritic cells (DCs), monocytes, and T lymphocytes. We have also detailed how lidocaine affects critical cellular processes, such as cellular polarization, cytokine production, phagocytosis, and apoptosis, through multiple signaling pathways, including NF-κB, TLR4/p38 MAPK, voltage-sensitive sodium channels, HIF1α, TGF-β/Smad3, AMPK-SOCS3, TBK1-IRF7, and G protein-coupled receptors. These immunoregulatory effects of lidocaine are dependent on its concentration, duration of action, and the microenvironment. The immunomodulatory actions of lidocaine may contribute to its potential therapeutic value in various settings of diseases, such as cancer, sepsis, acute lung injury, asthma, organ transplantation, ischemia–reperfusion injury (IRI), and diabetes. We propose that lidocaine can be repurposed as an immunomodulator for treating immune-mediated inflammatory diseases. However, future research should define optimal dosing strategies, validate its mechanisms of action in clinical trials, and explore its novel clinical applications as a complementary immunotherapy.