肿瘤微环境（TME）中的慢性炎症环境导致骨髓源性抑制细胞（MDSC）的募集和分化。多形核 (PMN)-MDSC 在表型和形态学上被定义为中性粒细胞的一个子集，在 TME 中引起主要的免疫抑制，对有效免疫疗法的开发提出了重大挑战。尽管最近我们对 PMN-MDSC 功能的理解取得了进展，但 TME 内产生免疫抑制性中性粒细胞的机制仍然难以捉摸。在体内和体外，新招募到肿瘤部位的中性粒细胞在几天内保持激活和高度运动性，并形成免疫抑制表型，如精氨酸酶 1 (Arg1) 和 dcTrail-R1 表达增加和抗癌 CD8 T 细胞细胞毒性抑制所示。通过在体外将幼稚中性粒细胞与癌细胞培养物上清液一起孵育，成功地重现了强抑制功能。对培养物上清液的癌症代谢物分泌组分析表明，小鼠和人类癌症均释放脂质介质以诱导免疫抑制性中性粒细胞的分化。液相色谱-质谱 (LC-MS) 脂质组学分析确定血小板激活因子（PAF；1-O-烷基-2-乙酰基-sn-甘油-3-磷酸胆碱）是一种常见的肿瘤来源的脂质介质，可诱导中性粒细胞分化。溶血磷脂酰胆碱酰基转移酶 2 (LPCAT2) 是一种 PAF 生物合成酶，在人胰腺导管腺癌 (PDAC) 中表达上调，并且与多种癌症类型的患者生存率呈不利相关。我们的研究确定 PAF 是 TME 中 MDSC 分化的脂质驱动机制，为癌症免疫治疗提供了潜在的靶点。

Chronic inflammatory milieu in the tumor microenvironment (TME) leads to the recruitment and differentiation of myeloid-derived suppressor cells (MDSCs). Polymorphonuclear (PMN)-MDSCs, which are phenotypically and morphologically defined as a subset of neutrophils, cause major immune suppression in the TME, posing a significant challenge in the development of effective immunotherapies. Despite recent advances in our understanding of PMN-MDSC functions, the mechanism that gives rise to immunosuppressive neutrophils within the TME remains elusive. Both in vivo and in vitro, newly recruited neutrophils into the tumor sites remained activated and highly motile for several days and developed immunosuppressive phenotypes, as indicated by increased arginase 1 (Arg1) and dcTrail-R1 expression and suppressed anticancer CD8 T cell cytotoxicity. The strong suppressive function was successfully recapitulated by incubating naive neutrophils with cancer cell culture supernatant in vitro. Cancer metabolite secretome analyses of the culture supernatant revealed that both murine and human cancers released lipid mediators to induce the differentiation of immunosuppressive neutrophils. Liquid chromatography-mass spectrometry (LC-MS) lipidomic analysis identified platelet-activation factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) as a common tumor-derived lipid mediator that induces neutrophil differentiation. Lysophosphatidylcholine acyltransferase 2 (LPCAT2), the PAF biosynthetic enzyme, is up-regulated in human pancreatic ductal adenocarcinoma (PDAC) and shows an unfavorable correlation with patient survival across multiple cancer types. Our study identifies PAF as a lipid-driven mechanism of MDSC differentiation in the TME, providing a potential target for cancer immunotherapy.