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Nur77 agonism invigorates Natural Killer cell immunity against hepatocellular carcinoma

Shi Yong Neo1,2, Yu Mei3,4, Joni Chong5

  • 1Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore. neo_shi_yong@a-star.edu.sg.

Nature Communications
|June 29, 2026
PubMed

Insights

Natural killer (NK) cells show promise for cancer therapy but struggle in solid tumors. Activating Nur77 enhances NK cell anti-tumor functions, improving immunotherapy for hepatocellular carcinoma (HCC).

Area of Science:

  • Immunology
  • Cancer Biology
  • Cellular Therapeutics

Background:

  • Natural killer (NK) cells are promising cancer therapeutics but face challenges in the solid tumor microenvironment (TME), including poor penetration and immunosuppression.
  • Hepatocellular carcinoma (HCC) remains a significant health concern, necessitating novel therapeutic strategies.

Purpose of the Study:

  • To investigate the role of Nur77 in NK cell-mediated immunity against HCC.
  • To explore Nur77 as a potential therapeutic target for enhancing NK cell immunotherapy in HCC.

Main Methods:

  • Spatial and single-cell transcriptomics analysis of human and mouse HCC tumors.
  • Conditional ablation and agonistic activation of Nur77 in NK cells.
  • Functional assays to assess NK cell proliferation, activation, and anti-tumor functions.
  • Analysis of CD36 expression and resistance to oxLDL-mediated immunosuppression.

Main Results:

  • NR4A1 (encoding Nur77) expression correlates with NK cell proliferation, AP-1 activation, and improved disease-free survival in HCC.
  • Nr4a1 ablation in NK cells accelerates tumor progression.
  • Nur77 activation enhances NK cell anti-tumor functions both ex-vivo and in-vivo.
  • Nur77 activation reduces CD36 expression and confers resistance to oxLDL-mediated immunosuppression.

Conclusions:

  • Nur77 plays a critical role in NK cell immunity against HCC.
  • Targeting Nur77 with agonistic therapies holds potential for improving NK cell-based immunotherapy for HCC.
  • Nur77 activation can overcome immunosuppression in the TME by modulating CD36 expression.

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