2. Academic Validation
  3. Secretogranin 2 binds LILRB4 resulting in immunosuppression

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

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. alec.zhang@utsouthwestern.edu.
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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