Nur77 agonism invigorates Natural Killer cell immunity against hepatocellular carcinoma

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. Nuclear receptor Nur77 is a transcription factor with immunomodulatory functions. Here, by integrating patient-derived samples, organoid co-cultures, and mouse models of hepatocellular carcinoma, the authors show that Nur77 promotes NK cell maturation and cytotoxicity by reducing lipid-mediated suppression and upregulating AP-1 response gene, and that Nur-77 agonism improves the response to adoptive NK cell therapy in HCC preclinical mouse models.

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Publication Details

Journal
Nature Communications
Published
2026-06-30
DOI
https://doi.org/10.1038/s41467-026-75027-3
Primary Topic
Nuclear Receptors and Signaling
Type
article
Field-Weighted Citation Impact
0.00

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article

Nur77 agonism invigorates Natural Killer cell immunity against hepatocellular carcinoma

Joni Chong, Subhra K. Biswas, Johan Hartman, Shiyong Neo et al.
Nature Communications
Nuclear Receptors and Signaling
article

Nur77 agonism invigorates Natural Killer cell immunity against hepatocellular carcinoma

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

Abstract

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. Nuclear receptor Nur77 is a transcription factor with immunomodulatory functions. Here, by integrating patient-derived samples, organoid co-cultures, and mouse models of hepatocellular carcinoma, the authors show that Nur77 promotes NK cell maturation and cytotoxicity by reducing lipid-mediated suppression and upregulating AP-1 response gene, and that Nur-77 agonism improves the response to adoptive NK cell therapy in HCC preclinical mouse models.

Nature Communications
Agency for Science, Technology and Research (SG), Karolinska University Hospital (SE), National University of Singapore (SG), Nanyang Technological University (SG), Medical University of Graz (AT), Singapore General Hospital (SG), Singapore Immunology Network (SG), Karolinska Institutet (SE), Duke-NUS Medical School (SG), National Cancer Centre Singapore (SG), Singapore-MIT Alliance for Research and Technology (SG), Institute of Molecular and Cell Biology (SG)
National Research Foundation, Agency for Science, Technology and Research, National Research Foundation Singapore, Karolinska Institutet, Karl-Franzens-Universität Graz, Medizinische Universität Graz, Medical Research Council, National Medical Research Council
Openalex Percentile: Top 11%
Nuclear Receptors and Signaling
DOIOpen Access PDFOpenAlex
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