SAMSN1 is a negative regulator of immune cell activation that functions as a checkpoint controlling both adaptive and innate immunity. The protein contains SAM and SH3 domains and localizes to the nucleus and cytoplasm, where it regulates actin cytoskeleton dynamics and modulates tyrosine kinase signaling. In B cells, SAMSN1 suppresses proliferation, but its broader immunosuppressive role has emerged from recent studies. In sepsis, SAMSN1 expression is elevated and associated with mortality; mechanistically, it binds KEAP1 to promote NRF2 nuclear translocation, driving expression of coinhibitory molecules (CD48, CD86, CEACAM1) on macrophages that induce T-cell exhaustion 1. In hepatocellular carcinoma, SAMSN1 is upregulated in intratumoral NK cells and suppresses granzyme B production; NK cell-specific deletion achieves 41% tumor burden reduction 2. Conversely, in glioblastoma, high SAMSN1 expression correlates with poor overall and progression-free survival 3, while in hepatocellular carcinoma and multiple myeloma, reduced SAMSN1 expression—driven by promoter hypermethylation—associates with malignant progression and worse prognosis 4, 5. In neonatal hypoxic-ischemic encephalopathy, SAMSN1 suppression enhances neuronal viability 6. These contradictory disease associations suggest context-dependent functions: SAMSN1 acts as a tumor suppressor in hematologic and hepatic malignancies but promotes immunosuppression in sepsis and solid tumors, positioning it as a potential therapeutic target through inhibition in cancer and sepsis contexts.