Year: 2026
Type: article
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.
Source: Nature Communications
Authors: 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
Institutions: Agency for Science, Technology and Research, Nanyang Technological University, Singapore Immunology Network, National University of Singapore, Life Sciences Institute, National Cancer Centre Singapore, Duke-NUS Medical School, Chinese Academy of Sciences, Karolinska Institutet, Shenzhen Institutes of Advanced Technology, Shenzhen Institute of Synthetic Biology, Singapore General Hospital, Institute of Molecular and Cell Biology, Karolinska University Hospital, Medical University of Graz, Singapore-MIT Alliance for Research and Technology, Mechanobiology Institute
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
OpenAlex ID: W7166587726
FWCI:
Cites:
Cited by:
Related to: