TNFAIP8L2 (TIPE2) functions as a critical negative regulator of both innate and adaptive immunity, maintaining immune homeostasis by inhibiting inflammatory responses 12. The protein suppresses T-cell receptor (TCR) and Toll-like receptor (TLR) signaling pathways, preventing hyperresponsive immune activation 3. Mechanistically, TNFAIP8L2 directly binds to and inhibits RAC1 GTPase activity, which disrupts the RAC1-MTOR complex and negatively regulates MTORC1 signaling 4. This interaction impairs autophagic lysosome reformation during prolonged starvation, affecting cellular autophagy processes 4. The protein is preferentially expressed in myeloid cells and shows dramatically decreased expression upon LPS stimulation 2. TNFAIP8L2 deficiency leads to heightened expression of genes involved in leukocyte activation and lipid biosynthesis, along with increased mitochondrial respiration rates 2. Clinically, abnormal TNFAIP8L2 expression is associated with various inflammatory diseases including asthma, colitis, and systemic lupus erythematosus 3. The protein's upregulation has been observed in inflammatory conditions such as polyethylene microplastic exposure 5, highlighting its role as an immune checkpoint regulator with potential therapeutic implications.