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; Ting Zhou

doi:10.1038/s41586-025-09202-9

Rescuing dendritic cell interstitial motility sustains antitumour immunity

Nature. 2025 Jun 25. doi: 10.1038/s41586-025-09202-9. Online ahead of print.

Authors

Haichao Tang^#^{1

2

3

4}, Zongfang Wei^#^{2

3

4}, Bei Zheng^{2

4}, Yumeng Cai⁵, Peihan Wu^{2

4}, Lulu Wu^{2

3

4}, Xiaohe Ma^{2

3

4}, Yanqin Chen^{2

4}, Si Su⁵, Jinmin Xu^{2

3

4}, Yu Qiao^{2

4}, Ying Zhang^{2

3

4}, Juju Miao^{2

3

4}, Zijing Yu^{2

4}, Yaodong Zhao^{2

3

4}, Zhen Xia^{2

4}, Rongjing Zhou⁶, Jian Liu⁷, Jufeng Guo⁷, Zhaoyuan Liu⁸, Qi Xie^{2

4}, Florent Ginhoux^{8

9}, Luming Zhao^{2

3

4}, Xu Li^{2

4}, Bing Xia⁶, Huanwen Wu⁵, Yongdeng Zhang^{2

4}, Ting Zhou^{10

11

12}

Affiliations

¹ School of Medicine, Zhejiang University, Hangzhou, China.
² Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.
³ School of Medicine, Westlake University, Hangzhou, China.
⁴ School of Life Sciences, Westlake University, Hangzhou, China.
⁵ Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
⁶ Hangzhou Cancer Hospital, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China.
⁷ Department of Breast Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China.
⁸ Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁹ Gustave Roussy Cancer Campus, Villejuif, France.
¹⁰ Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China. zhouting@westlake.edu.cn.
¹¹ School of Medicine, Westlake University, Hangzhou, China. zhouting@westlake.edu.cn.
¹² School of Life Sciences, Westlake University, Hangzhou, China. zhouting@westlake.edu.cn.

^# Contributed equally.

PMID: 40562926
DOI: 10.1038/s41586-025-09202-9

Abstract

The dendritic cell (DC)-initiated and sustained cancer immunity cycle is indispensable for effective endogenous and therapeutically mobilized antitumour T cell responses^1-8. 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.