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<p>Despite promising development as emerging “off-the-shelf” therapeutics against cancer, natural killer (NK) cells still faced considerable challenges in the solid tumor microenvironment (TME), including poor penetrance and immuno-suppression. Here, we employ spatial and single-cell transcriptomics to reveal a role for Nur77 in NK cell-mediated immunity against hepatocellular carcinoma (HCC). Orthogonal analysis of human and mouse HCC tumors indicate that the expression of <i>NR4A1</i>, encoding Nur77, is associated with NK cell proliferation, activation of the immunostimulatory AP-1 gene regulons, and better disease-free survival in HCC. Conditional ablation of <i>Nr4a1</i> in NK cells perturbs their homeostasis and accelerates tumor progression in multiple tumor models. Conversely, the agonistic activation of Nur77 in NK cells ex-vivo or in-vivo enhances their anti-tumor functions. Mechanistically, downstream functional assays confirm that Nur77 activation attenuates CD36 expression in NK cells and confers resistance against oxLDL-mediated immunosuppression in the TME. Collectively, our findings highlight the potential of harnessing Nur77 agonism in improving NK cell-based immunotherapy against HCC.</p>

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Nur77 agonism invigorates Natural Killer cell immunity against hepatocellular carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月30日

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  • Shi Yong Neo,
  • Yu Mei,
  • Joni Chong,
  • Kang Yi Lee,
  • Jyue Yuan Lim,
  • Menaka P. Rajapakse,
  • Timothy Wai Ho Shuen,
  • Junzhe Zhao,
  • Le Tong,
  • Tasneem Kajiji,
  • Hui Shi Cheong,
  • Charis Toh,
  • Zhen Wei Neo,
  • Li Yen Chong,
  • Wei Lin Tang,
  • Nicholas Ang,
  • Alicia Tay,
  • Xinsong Chen,
  • Hartman Johan,
  • Shanshan Wu Howland,
  • Joe Poh Sheng Yeong,
  • Subhra Kumar Biswas,
  • Elaine Lim,
  • Hanry Yu,
  • Shengli Xu,
  • Han Chong Toh,
  • Haiyan Liu,
  • Kong-Peng Lam

摘要

Despite promising development as emerging “off-the-shelf” therapeutics against cancer, natural killer (NK) cells still faced considerable challenges in the solid tumor microenvironment (TME), including poor penetrance and immuno-suppression. Here, we employ spatial and single-cell transcriptomics to reveal a role for Nur77 in NK cell-mediated immunity against hepatocellular carcinoma (HCC). Orthogonal analysis of human and mouse HCC tumors indicate that the expression of NR4A1, encoding Nur77, is associated with NK cell proliferation, activation of the immunostimulatory AP-1 gene regulons, and better disease-free survival in HCC. Conditional ablation of Nr4a1 in NK cells perturbs their homeostasis and accelerates tumor progression in multiple tumor models. Conversely, the agonistic activation of Nur77 in NK cells ex-vivo or in-vivo enhances their anti-tumor functions. Mechanistically, downstream functional assays confirm that Nur77 activation attenuates CD36 expression in NK cells and confers resistance against oxLDL-mediated immunosuppression in the TME. Collectively, our findings highlight the potential of harnessing Nur77 agonism in improving NK cell-based immunotherapy against HCC.