CD300ld on pathologically activated neutrophils promotes tumor immune suppression by binding phosphatidylserine on CD8+ T cells PMID: 42141174

ADC Targets in Oncology

2026-04-10

CD300ld on pathologically activated neutrophils promotes tumor immune suppression by binding phosphatidylserine on CD8+ T cells

Nat Cancer. 2026 May 15. doi: 10.1038/s43018-026-01169-4.

Chaoxiong Wang ^# ¹ ² , Peixuan Zheng ^# ¹ , Anhui Wang ^# ³ , Xinrui Fan ^# ¹ , Tianxiang Li ^# ¹ , Jingjing Hong ¹ , Runze Wang ¹ , Chunyan Zhang ¹ , Chaogui Luo ¹ , Weiwei Yang ¹ , Dong Gao ¹ , Adili Salai ⁴ , Min Luo ⁵ , Zhigang Lu ⁵ , Dianfan Li ⁶ , Moubin Lin ⁷ , Jiayin Peng ⁸ , Guohui Li ⁹ , Shuo Han ¹⁰ , Yun Zhao ¹¹ ¹² ¹³

Affiliations

1. Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
2. College of Basic Medicine, Inner Mongolia Medical University, Hohhot, China.
3. Interdisciplinary Research Center for Biology and Chemistry, Liaoning Normal University, Dalian, China.
4. Second Department of Thoracic Surgery, Tumor Hospital Affiliated to Xinjiang Medical University, Wulumuqi, China.
5. Institute of Pediatrics of Children's Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
6. School of Agriculture and Biotechnology, Sun Yat-Sen University, Shenzhen, China. [email protected].
7. Center for Clinical Research and Translational Medicine, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China. [email protected].
8. Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. [email protected].
9. Interdisciplinary Research Center for Biology and Chemistry, Liaoning Normal University, Dalian, China. [email protected].
10. Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. [email protected].
11. Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. [email protected].
12. School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
13. School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. [email protected].
# Contributed equally.

Abstract

The immunosuppressive tumor microenvironment remains a major obstacle to successful immunotherapy. Pathologically activated neutrophils, alternatively termed polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), drive tumor immune evasion primarily by inducing CD8⁺ T cell tolerance. While direct intercellular contact between neutrophils and CD8⁺ T cells is essential for immunosuppressive activity, the mechanisms mediating this interaction need deeper understanding. We previously reported that CD300ld is required for recruiting PMN-MDSCs into tumors, suppressing T cell activation. Here we show that CD300ld mediates neutrophil-driven contact-dependent suppression of cytotoxic CD8⁺ T cells by binding to phosphatidylserine (PS). Mice with mutant CD300ld lacking PS-binding capacity exhibit reduced immunosuppressive activity. Blockade of the CD300ld-PS interaction by neutralizing antibodies demonstrates therapeutic efficacy against established tumors and synergizes with anti-PD1. Our findings establish CD300ld-PS-mediated cell contact as a critical mechanism of neutrophil-driven immune evasion, revealing a targetable checkpoint pathway to overcome tumor immune resistance and improve immunotherapy outcomes.