2025年8月7日出版的《癌细胞》杂志发表了南京大学魏嘉课题组的最新成果，他们的最新研究报道了CHI3L3⁺未成熟中性粒细胞抑制骨转移的抗肿瘤免疫并阻碍免疫检查点阻断治疗。

课题组观察到未成熟中性粒细胞在骨转移微环境中的优势，无论是motheme模型还是癌症患者。Dickkopf1 （DKK1）在中性粒细胞中诱导一种不成熟的功能状态，中性粒细胞表现出强烈的免疫抑制能力，抑制CD8⁺ T细胞的抗肿瘤反应。在机制上，DKK1-CKAP4-STAT6信号通路驱动CHI3L3的表达，这是骨转移中未成熟中性粒细胞介导的免疫抑制所必需的。

此外，阻断DKK1可促进中性粒细胞成熟，改善免疫微环境，诱导肿瘤缩小，并在多发性骨转移模型中增强ICB治疗反应。这些发现揭示了未成熟中性粒细胞在骨转移中的关键作用，并提出了调节中性粒细胞以改善癌症免疫治疗的潜在策略。

研究人员表示，骨转移瘤仍然无法治愈，对免疫检查点阻断（ICB）治疗反应不佳。中性粒细胞成熟对癌症的影响，特别是对包括骨转移在内的难治性肿瘤的影响，目前还不清楚。

附：英文原文

Title: CHI3L3+ immature neutrophils inhibit anti-tumor immunity and impede immune checkpoint blockade therapy in bone metastases

Author: Tao Shi, Wei Liu, Yuting Luo, Kaijie Liang, Shiji Ren, Xueru Song, Fangcen Liu, Chun Lu, Daniel Hirschhorn, Hanbing Wang, Yipeng Zhang, Yiran Cai, Yue Wang, Yunfeng Pan, Wenqi Liu, Yang Nie, Ziliang Zhang, Lixia Yu, Shuai Ding, Baorui Liu, Taha Merghoub, Yan Li, Jia Wei

Issue&Volume: 2025-08-07

Abstract: Bone metastases remain incurable and respond poorly to immune checkpoint blockade (ICB) therapy. The impact of neutrophil maturation in cancer, particularly in refractory tumors including bone metastases, is not well understood. Here, we observed the predominance of immature neutrophils in the bone metastasis microenvironment of both mouse models and cancer patients. Dickkopf1 (DKK1) induces an immature-like functional state in neutrophils, which exhibit robust immunosuppressive capabilities to inhibit anti-tumor response of CD8+ T cells. Mechanistically, the DKK1-CKAP4-STAT6 signaling pathway drives CHI3L3 expression, which is necessary for the immune suppression mediated by immature neutrophils in bone metastases. Moreover, blocking DKK1 promotes neutrophil maturation to improve the immune microenvironment, induces tumor shrinkage, and enhances ICB therapy response in multiple bone metastasis mouse models. These findings uncover a critical role for immature neutrophils in bone metastases and suggest a potential strategy for modulating neutrophils to improve cancer immunotherapy.

DOI: 10.1016/j.ccell.2025.07.007

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00313-7