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<p>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<sup>+</sup> T cell tolerance. While direct intercellular contact between neutrophils and CD8<sup>+</sup> 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<sup>+</sup> 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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年5月15日

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  • Chaoxiong Wang,
  • Peixuan Zheng,
  • Anhui Wang,
  • Xinrui Fan,
  • Tianxiang Li,
  • Jingjing Hong,
  • Runze Wang,
  • Chunyan Zhang,
  • Chaogui Luo,
  • Weiwei Yang,
  • Dong Gao,
  • Adili Salai,
  • Min Luo,
  • Zhigang Lu,
  • Dianfan Li,
  • Moubin Lin,
  • Jiayin Peng,
  • Guohui Li,
  • Shuo Han,
  • Yun Zhao

摘要

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.