SAMSN1 is a multifunctional immune regulator that acts primarily as a negative checkpoint on adaptive and innate immunity. As a negative regulator of B-cell activation 1, SAMSN1 suppresses immune responses through distinct mechanisms in different cell types. In macrophages, SAMSN1 binds KEAP1 to disrupt the KEAP1-NRF2 complex, promoting nuclear NRF2 translocation and upregulation of coinhibitory molecules (CD48, CD86, CEACAM1) that drive T-cell exhaustion and immunosuppression in sepsis 1. In NK cells, SAMSN1 functions as an immune checkpoint that restrains anti-tumor immunity in hepatocellular carcinoma by suppressing NK cell activation, proliferation, and granzyme B production 2. The gene exhibits opposing roles in cancer: it is downregulated in hepatocellular carcinoma and acts as a tumor suppressor through promoter hypermethylation 3, but is upregulated in glioblastoma where high expression correlates with poor prognosis 4. In neonatal brain injury, SAMSN1 upregulation is detrimental, and its silencing provides neuroprotection by enhancing neuronal cell viability 5. As a differentiation-related gene in tumor-associated macrophages, SAMSN1 downregulation associates with better prognosis in lung adenocarcinoma 6. SAMSN1 deletion in multiple myeloma models substantially reduces tumor burden, though some effects involve host immune-mediated graft rejection 78.