TY - JOUR
T1 - Rescuing dendritic cell interstitial motility sustains antitumour immunity
AU - Tang, Haichao
AU - Wei, Zongfang
AU - Zheng, Bei
AU - Cai, Yumeng
AU - Wu, Peihan
AU - Wu, Lulu
AU - Ma, Xiaohe
AU - Chen, Yanqin
AU - Su, Si
AU - Xu, Jinmin
AU - Qiao, Yu
AU - Zhang, Ying
AU - Miao, Juju
AU - Yu, Zijing
AU - Zhao, Yaodong
AU - Xia, Zhen
AU - Zhou, Rongjing
AU - Liu, Jian
AU - Guo, Jufeng
AU - Liu, Zhaoyuan
AU - Xie, Qi
AU - Ginhoux, Florent
AU - Zhao, Luming
AU - Li, Xu
AU - Xia, Bing
AU - Wu, Huanwen
AU - Zhang, Yongdeng
AU - Zhou, Ting
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2025.
PY - 2025/1/1
Y1 - 2025/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=105008916880&partnerID=8YFLogxK
U2 - 10.1038/s41586-025-09202-9
DO - 10.1038/s41586-025-09202-9
M3 - Article
AN - SCOPUS:105008916880
SN - 0028-0836
JO - Nature
JF - Nature
ER -