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<p>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 (<i>Samsn1</i><sup>−/−</sup>) mice exhibits 34% tumor burden reduction with enhanced NK cell granzyme B production (<i>P</i> = 0.0002). Critically, NK cell-specific deletion alone (<i>Samsn1</i><sup><i>f/f</i></sup><i>-Ncr1</i><sup><i>Cre+</i></sup>) recapitulates this therapeutic effect (41% tumor burden reduction, <i>P</i> = 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月21日

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  • Ruifeng Wang,
  • Huidi Chen,
  • Hanyang Liu,
  • Qiang Li,
  • Guojing Yao,
  • Fuling Li,
  • Peng Sun,
  • Tianli Dai,
  • Jiabei Wang,
  • Björn Nashan,
  • Cheng Sun

摘要

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.