Rescuing dendritic cell interstitial motility sustains antitumour immunity

• 成果类型: Article
• 署名作者: 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
• 署名单位: Zhejiang University; Westlake Laboratory; Westlake University; Westlake University; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College; Peking Union Medical College Hospital; Westlake University; Westlake University; Shanghai Jiao Tong University; Chinese Academy of Sciences; UNICANCER; Gustave Roussy
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2725
• DOI: 10.1038/s41586-025-09202-9
• 发表日期: 2025-09-04
• 关键词: myosin-ii; cgmp; migration; adhesion; head; phosphodiesterases; identification; population; immunology; mechanisms

摘要

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.