LAG3 (lymphocyte activating 3) is an immune checkpoint receptor that functions as a negative regulator of T cell activation and immune responses. LAG3 binds to MHC class II molecules on antigen-presenting cells and undergoes ligand-induced non-K48-linked polyubiquitination mediated by E3 ligases c-Cbl and Cbl-b, which disrupts membrane sequestration of its cytoplasmic signaling motifs and enables its inhibitory function 1. The protein contributes to T cell exhaustion in tumor microenvironments through sustained expression following persistent antigen exposure, resulting in impaired T cell proliferation and cytokine production 2. LAG3 shows striking synergy with PD-1 in multiple settings, and dual LAG3/PD-1 blockade provides superior clinical outcomes compared to PD-1 inhibition alone in melanoma patients 3. Beyond cancer immunotherapy, LAG3 is expressed in atherosclerotic plaques where it mediates immune cell interactions that can be affected by cardiometabolic factors 4. LAG3 expression on exhausted CD8+ T cells correlates with immunotherapy resistance in lung adenocarcinoma 5. Additionally, LAG3 facilitates pathologic α-synuclein transmission in neurodegeneration through interaction with Aplp1, suggesting roles beyond immune regulation 6. The clinical significance of LAG3 is underscored by FDA-approved combination therapies targeting both LAG3 and PD-1 pathways 7.