SAMSN1 restrains NK cell mediated anti-tumor immunity in hepatocellular carcinoma

NK cells are critical mediators of anti-tumor immunity whose function is frequently compromised in the tumor microenvironment. Here we identify SAM domain, SH3 domain and nuclear localization signals 1 (SAMSN1) as a previously unrecognized immune checkpoint that predominantly regulates NK cell function in hepatocellular carcinoma (HCC). Single-cell RNA sequencing (scRNA-seq) analysis reveals significant SAMSN1 upregulation in intratumoral NK cells from HCC patients, correlating with reduced granzyme B expression and poor prognosis. In orthotopic Hepa1-6 hepatocellular carcinoma models, global Samsn1 knockout (Samsn1−/−) mice exhibits 34% tumor burden reduction with enhanced NK cell granzyme B production (P = 0.0002). Critically, NK cell-specific deletion alone (Samsn1f/f-Ncr1Cre+) recapitulates this therapeutic effect (41% tumor burden reduction, P = 0.0017), demonstrating that SAMSN1 functions predominantly through intratumoral NK cells rather than other immune populations in the HCC microenvironment. Mechanistically, SAMSN1 suppresses NK cell activation, proliferation, and granzyme B production. These findings indicate SAMSN1 as a targetable NK cell checkpoint with direct therapeutic implications for HCC immunotherapy. NK cell dysfunction in tumor microenvironment remains elusive. The authors here identify SAMSN1 as an immune checkpoint that mediates NK function. Specifically, global or NK cell-specific deletion of SAMSN1 restores NK function and improves prognosis in hepatocellular carcinoma mouse models.