趋化因子在肿瘤局部免疫反应中扮演着重要角色。CCL17和CCL22能够吸引CCr4阳性细胞，介入肿瘤的免疫环境，但它们在肿瘤中的直接作用和功能状态仍不清楚。我们分析了淋巴瘤相关的单细胞RNA测序和批量RNA测序数据集，并确定了CCL17/CCL22-CCR4轴是肿瘤微环境中唯一的参与者。然后，我们编辑了A20淋巴瘤细胞系，使其表达CCL17和CCL22，并使用三种小鼠模型（Balb/C小鼠、裸鼠和NSG小鼠）评估其功能。此外，我们回顾性地检查了CCL17/CCL22-CCR4轴与癌症患者存活率之间的关系。活跃的CCL17/CCL22-CCR4轴是霍奇金淋巴瘤微环境的显著特征。CCR4在免疫细胞中广泛表达，但在NK、NKT和Treg细胞表面高度存在。Balb/C小鼠的肿瘤模型表明，CCL17充当由激活的T细胞反应介导的抗肿瘤趋化素。此外，裸鼠肿瘤模型显示，CCL17招募NK细胞抑制淋巴瘤生长，并增强NK-cDC1的相互作用以抵抗IL4i1介导的免疫抑制。有趣的是，CCL17介导的抗肿瘤免疫反应依赖于淋巴样系，而不是主要的髓样系。此外，我们发现CCL17/CCL22-CCR4轴不能被视为大多数癌症类型预后不良的生物标记物。我们提供了CCL17介导的抗肿瘤功能，通过招募常规T细胞、NKT细胞和NK细胞的直接证据。目标基因（CCL17、CCL22和CCR4）表达的临床生存结局也表明，CCL17/CCL22-CCR4轴不是预后不良的标志。 版权所有 ©2023 Elsevier B.V.。

Chemokines are critical players in the local immune responses to tumors. CCL17 (thymus and activation-regulated chemokine, TARC) and CCL22 (macrophage-derived chemokine, MDC) can attract CCR4-bearing cells involving the immune landscape of cancer. However, their direct roles and functional states in tumors remain largely unclear.We analyzed the lymphoma-related scRNA-seq and bulk RNA-seq datasets and identified the CCL17/CCL22-CCR4 axis as the unique participant of the tumor microenvironment. Then we edited the A20 lymphoma cell line to express CCL17 and CCL22 and assessed their function using three mouse models (Balb/C mouse, Nude mouse, and NSG mouse). In addition, we retrospectively checked the relationship between the CCL17/CCL22-CCR4 axis and the survival rates of cancer patients.The active CCL17/CCL22-CCR4 axis is a distinctive feature of the Hodgkin lymphoma microenvironment. CCR4 is widely expressed in immune cells but highly exists on the surface of NK, NKT, and Treg cells. The tumor model of Balb/C mice showed that CCL17 acts as an anti-tumor chemokine mediated by activated T cell response. In addition, the tumor model of Nude mice showed that CCL17 recruits NK cells for inhibiting lymphoma growth and enhances the NK-cDC1 interaction for resisting IL4i1-mediated immunosuppression. Interestingly, CCL17-mediated antitumor immune responses depend on lymphoid lineages but not mainly myeloid ones. Furthermore, we found CCL17/CCL22-CCR4 axis cannot be regarded as biomarkers of poor prognosis in most cancer types from the TCGA database.We provided direct evidence of antitumor functions of CCL17 mediated by the recruitment of conventional T cells, NKT cells, and NK cells. Clinical survival outcomes of target gene (CCL17, CCL22, and CCR4) expression also identified that CCL17/CCL22-CCR4 axis is not a marker of poor prognosis.Copyright © 2023 Elsevier B.V. All rights reserved.