SAMSN1 抑制肝细胞癌中 NK 细胞介导的抗肿瘤免疫

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.