NKp46 enhances type 1 innate lymphoid cell proliferation and function and anti-acute myeloid leukemia activity

Rui Ma, Zhenlong Li, Hejun Tang, Xiaojin Wu, Lei Tian, Zahir Shah, Ningyuan Liu, Tasha Barr, Jianying Zhang, Sean Wang, Srividya Swaminathan, Guido Marcucci, Yong Peng (), Michael A. Caligiuri () and Jianhua Yu ()
Additional contact information
Rui Ma: Sichuan University
Zhenlong Li: City of Hope National Medical Center
Hejun Tang: City of Hope National Medical Center
Xiaojin Wu: The First Affiliated Hospital of Soochow University
Lei Tian: University of California
Zahir Shah: City of Hope National Medical Center
Ningyuan Liu: City of Hope National Medical Center
Tasha Barr: City of Hope National Medical Center
Jianying Zhang: City of Hope National Medical Center
Sean Wang: City of Hope National Medical Center
Srividya Swaminathan: City of Hope Beckman Research Institute
Guido Marcucci: City of Hope National Medical Center
Yong Peng: Sichuan University
Michael A. Caligiuri: City of Hope National Medical Center
Jianhua Yu: University of California

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract NKp46 is a critical regulator of natural killer (NK) cell immunity, but its function in non-NK innate immune cells remains unclear. Here, we show that NKp46 is indispensable for expressing IL-2 receptor-α (IL-2Rα) by non-NK liver-resident type-1 innate lymphoid cells (ILC1s). Deletion of NKp46 reduces IL-2Rα on ILC1s by downregulating NF-κB signaling, thus impairing ILC1 proliferation and cytotoxicity in vitro and in vivo. The binding of anti-NKp46 antibody to NKp46 triggers the activation of NF-κB, the expression of IL-2Rα, interferon-γ (IFN-γ), tumor necrosis factor (TNF), proliferation, and cytotoxicity. Functionally, NKp46 expressed on mouse ILC1s interacts with tumor cells through cell–cell contact, increasing ILC1 production of IFN-γ and TNF, and enhancing cytotoxicity. In a mouse model of acute myeloid leukemia, deletion of NKp46 impairs the ability of ILC1s to control tumor growth and reduces survival. This can be reversed by injecting NKp46+ ILC1s into NKp46 knock-out mice. Human NKp46+ ILC1s exhibit stronger cytokine production and cytotoxicity than their NKp46− counterparts, suggesting that NKp46 plays a similar role in humans. These findings identify an NKp46–NF-κB–IL-2Rα axis and suggest that activating NKp46 with an anti-NKp46 antibody may provide a potential strategy for anti-tumor innate immunity.

Date: 2025
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DOI: 10.1038/s41467-025-55923-w

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