Rescuing dendritic cell interstitial motility sustains antitumour immunity

Haichao Tang, Zongfang Wei, Bei Zheng, Yumeng Cai, Peihan Wu, Lulu Wu, Xiaohe Ma, Yanqin Chen, Si Su, Jinmin Xu, Yu Qiao, Ying Zhang, Juju Miao, Zijing Yu, Yaodong Zhao, Zhen Xia, Rongjing Zhou, Jian Liu, Jufeng Guo, Zhaoyuan Liu, Qi Xie, Florent Ginhoux, Luming Zhao, Xu Li, Bing Xia, Huanwen Wu, Yongdeng Zhang and Ting Zhou ()
Additional contact information
Haichao Tang: Zhejiang University
Zongfang Wei: Westlake Laboratory of Life Sciences and Biomedicine
Bei Zheng: Westlake Laboratory of Life Sciences and Biomedicine
Yumeng Cai: Chinese Academy of Medical Sciences and Peking Union Medical College
Peihan Wu: Westlake Laboratory of Life Sciences and Biomedicine
Lulu Wu: Westlake Laboratory of Life Sciences and Biomedicine
Xiaohe Ma: Westlake Laboratory of Life Sciences and Biomedicine
Yanqin Chen: Westlake Laboratory of Life Sciences and Biomedicine
Si Su: Chinese Academy of Medical Sciences and Peking Union Medical College
Jinmin Xu: Westlake Laboratory of Life Sciences and Biomedicine
Yu Qiao: Westlake Laboratory of Life Sciences and Biomedicine
Ying Zhang: Westlake Laboratory of Life Sciences and Biomedicine
Juju Miao: Westlake Laboratory of Life Sciences and Biomedicine
Zijing Yu: Westlake Laboratory of Life Sciences and Biomedicine
Yaodong Zhao: Westlake Laboratory of Life Sciences and Biomedicine
Zhen Xia: Westlake Laboratory of Life Sciences and Biomedicine
Rongjing Zhou: Westlake University
Jian Liu: Westlake University
Jufeng Guo: Westlake University
Zhaoyuan Liu: Shanghai Jiao Tong University School of Medicine
Qi Xie: Westlake Laboratory of Life Sciences and Biomedicine
Florent Ginhoux: Shanghai Jiao Tong University School of Medicine
Luming Zhao: Westlake Laboratory of Life Sciences and Biomedicine
Xu Li: Westlake Laboratory of Life Sciences and Biomedicine
Bing Xia: Westlake University
Huanwen Wu: Chinese Academy of Medical Sciences and Peking Union Medical College
Yongdeng Zhang: Westlake Laboratory of Life Sciences and Biomedicine
Ting Zhou: Westlake Laboratory of Life Sciences and Biomedicine

Nature, 2025, vol. 645, issue 8079, 244-253

Abstract: Abstract The dendritic cell (DC)-initiated and sustained cancer immunity cycle is indispensable for effective endogenous and therapeutically mobilized antitumour T cell responses1–8. This necessitates the continuous migration of antigen-carrying DCs from the tumour microenvironment (TME) to the tumour draining lymph nodes (tdLNs)7–13. 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.

Date: 2025
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DOI: 10.1038/s41586-025-09202-9

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