免疫抑制性肿瘤微环境是有效免疫疗法的主要障碍之一1,2。病理活化性中性粒细胞，也被称为多形核粒白血细胞来源的抑制性细胞（PMN-MDSCs），是肿瘤微环境的关键组成部分，在肿瘤进展和治疗抵抗方面发挥着重要作用2-4。需要确定PMN-MDSCs上的关键分子，以有选择性地针对这些细胞进行肿瘤治疗。在这里，我们在肿瘤小鼠模型中进行了体内CRISPR-Cas9筛选，并确定CD300ld作为顶级肿瘤有利受体的候选者。CD300ld在正常中性粒细胞中特异性表达，并在PMN-MDSCs在肿瘤携带时上调。CD300ld的敲除以PMN-MDSC依赖的方式抑制了多种肿瘤类型的发展。CD300ld对PMN-MDSCs进入肿瘤和抑制T细胞活化的作用是必需的。CD300ld通过STAT3-S100A8/A9轴发挥作用，敲除Cd300ld可以逆转肿瘤免疫抑制性微环境。CD300ld在人类肿瘤中上调，并与患者生存不利相关。阻断CD300ld活性抑制肿瘤的发展，并与抗PD1有协同效应。我们的研究确定了CD300ld作为PMN-MDSCs上的重要免疫抑制因子，对肿瘤免疫抵抗具有必要性，并为癌症免疫治疗提供了潜在的靶标。© 2023. 作者，独家授权给施普林格自然有限公司。

The immune-suppressive tumour microenvironment represents a major obstacle to effective immunotherapy1,2. Pathologically activated neutrophils, also known as polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), are a critical component of the tumour microenvironment and have crucial roles in tumour progression and therapy resistance2-4. Identification of the key molecules on PMN-MDSCs is required to selectively target these cells for tumour treatment. Here, we performed an in vivo CRISPR-Cas9 screen in a tumour mouse model and identified CD300ld as a top candidate of tumour-favouring receptors. CD300ld is specifically expressed in normal neutrophils and is upregulated in PMN-MDSCs upon tumour-bearing. CD300ld knockout inhibits the development of multiple tumour types in a PMN-MDSC-dependent manner. CD300ld is required for the recruitment of PMN-MDSCs into tumours and their function to suppress T cell activation. CD300ld acts via the STAT3-S100A8/A9 axis, and knockout of Cd300ld reverses the tumour immune-suppressive microenvironment. CD300ld is upregulated in human cancers and shows an unfavourable correlation with patient survival. Blocking CD300ld activity inhibits tumour development and has synergistic effects with anti-PD1. Our study identifies CD300ld as a critical immune suppressor present on PMN-MDSCs, being required for tumour immune resistance and providing a potential target for cancer immunotherapy.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.