Secretogranin 2 binds LILRB4 resulting in immunosuppression

  • Nat Immunol. 2025 Sep;26(9):1567-1580. doi: 10.1038/s41590-025-02233-4.
Xing Yang  1 ,  Ryan Huang  1 ,  Meng Fang  1 ,  Yubo He  1 ,  Jingjing Xie  1 ,  Xiaoye Liu  1 ,  Chengcheng Zhang  1 ,  Qi Lou  1 ,  Mi Deng  1 ,  Wei Xiong  2 ,  Cheryl Lewis  3 ,  Zade Sadek  1 ,  Ankit Gupta  4 ,  Lianqi Chen  5 ,  Xuewu Zhang  5 ,  Lei Guo  6 ,  Lin Xu  6 ,  Ningyan Zhang  2 ,  Zhiqiang An  2 ,  Cheng Cheng Zhang  7
Affiliations
  • 1. Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 2. Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX, USA.
  • 3. Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 4. Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 5. Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 6. Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 7. Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. [email protected].
PMID: 40707822 DOI: 10.1038/s41590-025-02233-4
Abstract

Immunosuppressive myeloid cells are important in a variety of physiological and pathological contexts, including tumor development, but how Hormones might regulate their activity is unclear. Secretogranins, a family of secretory proteins in endocrine and neuronal cells, are proposed to function as prohormones or Hormones, but their specific receptors are unknown. Here we show that secretogranin 2 (SCG2), a granin family member, functionally interacts with leukocyte immunoglobulin-like receptor B4 (LILRB4) on monocytic cells. Tumor-derived SCG2 promotes tumor growth in myeloid-specific LILRB4 transgenic mice in a T cell-dependent manner, whereas SCG2 deficiency in host mice impairs tumor progression and reduces infiltration of immunosuppressive monocytic cells. Blockade of LILRB4 abrogates SCG2-induced signaling, immunosuppression and tumor growth. Mechanistically, this SCG2-LILRB4 interaction triggers SHP recruitment and SHP-independent STAT3 activation. These findings define a function for SCG2 in regulating monocytic immunosuppression and suggest that the SCG2-LILRB4 axis might be a therapeutic target.

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