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 (Samsn1^f/f-Ncr1^Cre+) 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.