西湖大学周挺团队近日取得一项新成果。经过不懈努力，他们的研究显示，挽救树突状细胞间质运动维持抗肿瘤免疫。相关论文发表在2025年6月25日出版的《自然》杂志上。

通过对人类和母鼠肿瘤的纵向分析，该研究团队观察到tdLN中迁移性常规DC（mig-cDCs）在肿瘤进展过程中逐渐减少。这种下降损害了肿瘤特异性T细胞启动和随后的T细胞对TME的供应。利用全基因组的体内CRISPR筛选，该课题组人员发现磷酸二酯酶5 （PDE5）及其底物环鸟苷单磷酸（cGMP）是DC迁移的关键调节剂。晚期肿瘤破坏了DC中cGMP的合成，降低了它们的运动能力，而PDE5的扰动保留了cGMP库，恢复了DC的迁移。从机制上讲，cGMP通过Rho相关因子增强了肌球蛋白- ii活性，扩展了cGMP调节的变形虫从盘基骨柱向哺乳动物免疫细胞迁移的模式。PDE5主题西地那非的药理学抑制恢复了mig-cDC对晚期tdLN的归巢，并以DC依赖的方式维持了抗肿瘤免疫。他们的发现将基本的DC间质运动与抗肿瘤免疫联系起来，揭示了其在混乱TME中的破坏促进了免疫逃避，其增强为DC中心免疫治疗提供了一个有希望的方向。

据介绍，树突状细胞（DC）发起和维持的癌症免疫周期对于有效的内源性和治疗性动员的抗肿瘤T细胞反应是必不可少的。这就需要携带抗原的DC从肿瘤微环境（TME）持续迁移到肿瘤引流淋巴结（tdLN）。

附：英文原文

Title: Rescuing dendritic cell interstitial motility sustains antitumour immunity

Author: Tang, Haichao, Wei, Zongfang, Zheng, Bei, Cai, Yumeng, Wu, Peihan, Wu, Lulu, Ma, Xiaohe, Chen, Yanqin, Su, Si, Xu, Jinmin, Qiao, Yu, Zhang, Ying, Miao, Juju, Yu, Zijing, Zhao, Yaodong, Xia, Zhen, Zhou, Rongjing, Liu, Jian, Guo, Jufeng, Liu, Zhaoyuan, Xie, Qi, Ginhoux, Florent, Zhao, Luming, Li, Xu, Xia, Bing, Wu, Huanwen, Zhang, Yongdeng, Zhou, Ting

Issue&Volume: 2025-06-25

Abstract: The dendritic cell (DC)-initiated and sustained cancer immunity cycle is indispensable for effective endogenous and therapeutically mobilized antitumour T cell responses1,2,3,4,5,6,7,8. This necessitates the continuous migration of antigen-carrying DCs from the tumour microenvironment (TME) to the tumour draining lymph nodes (tdLNs)7,8,9,10,11,12,13. Here, through longitudinal analysis of human and mouse tumours, we observed a progressive decrease in migratory conventional DCs (mig-cDCs) in the tdLNs during tumour progression. This decline compromised tumour-specific T cell priming and subsequent T cell supply to the TME. Using a genome-wide in vivo CRISPR screen, we identified phosphodiesterase 5 (PDE5) and its substrate cyclic guanosine monophosphate (cGMP) as key modulators of DC migration. Advanced tumours disrupted cGMP synthesis in DCs to decrease their motility, while PDE5 perturbation preserved the cGMP pool to restore DC migration. Mechanistically, cGMP enhanced myosin-II activity through Rho-associated factors, extending the paradigm of cGMP-regulated amoeboid migration from Dictyostelium to mammalian immune cells. Pharmacological inhibition of PDE5 using sildenafil restored mig-cDC homing to late-stage tdLNs and sustained antitumour immunity in a DC-dependent manner. Our findings bridge fundamental DC interstitial motility to antitumour immunity, revealing that its disruption in chaotic TME promotes immune evasion, and its enhancement offers a promising direction for DC-centric immunotherapy.

DOI: 10.1038/s41586-025-09202-9

Source: https://www.nature.com/articles/s41586-025-09202-9