FGL1 (fibrinogen-like protein 1) is an immune suppressive molecule that functions as a major ligand of the LAG-3 immune checkpoint receptor. FGL1 inhibits antigen-specific T-cell activation by binding LAG-3 independently of MHC class II 1, triggering LAG-3 ubiquitination that stabilizes its inhibitory signaling conformation 2. Upon ligand engagement, LAG-3 undergoes non-K48-linked polyubiquitination mediated by E3 ligases c-Cbl and Cbl-b, disrupting membrane sequestration of signaling motifs 2. FGL1 is secreted by hepatocytes and cancer cells, promoting hepatocyte growth 34. In cancer contexts, FGL1 mediates immune evasion through multiple mechanisms: elevated plasma FGL1 correlates with poor prognosis and resistance to anti-PD-1 therapy 1. In colorectal cancer liver metastases, tumor-associated macrophages activate NF-κB to upregulate OTUD1, which stabilizes FGL1 through deubiquitination, reducing T-cell infiltration 5. FGL1 also regulates acquired gefitinib resistance in NSCLC by inhibiting apoptosis via the PARP1/caspase-3 pathway 6. HDAC inhibitor SAHA enhances antitumor immunity by suppressing FGL1 through the HDAC1/JAK1 axis 7. These findings position FGL1/LAG-3 as an emerging immunotherapy target comparable to PD-1/PD-L1 8.