[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-434515-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-434515-en":130},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","restoring-dendritic-cell-interstitial-motility-via-pde5-inhibition-for-sustained-antitumor-immunity-commentary","Restoring dendritic cell interstitial motility via PDE5 inhibition for sustained antitumor immunity - Commentary","","Commentary summarizes a Nature study identifying cyclic guanosine monophosphate (cGMP) as a key PDE5 substrate controlling dendritic cell (DC) interstitial motility through Rho kinase (ROCK)-dependent regulation of myosin-II activity. The discussion explains how PDE5 inhibition with sildenafil restores migratory conventional DCs homing to tumor draining lymph nodes, enhances T cell priming and activation, and improves tumor control and survival in tumor-bearing models. It also highlights synergy with anti-PD-1 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control.",{"name":70,"@type":61,"acceptedAnswer":71},"Why does the combined treatment with sildenafil and anti-PD-1 perform better than monotherapy?",{"text":72,"@type":64},"The commentary reports synergistic antitumor efficacy, with combined therapy showing substantially higher cure rates than anti-PD-1 alone or sildenafil alone, revitalizing both DC function and T cell responses.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},434515,1790926952,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,100,105,109,114,119,122,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & 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\nJournal of the National Cancer Center  \njournal [homepage:](homepage: www.elsevier.com/locate/jncc)[ www.elsevier.com/locate/jncc](homepage: www.elsevier.com/locate/jncc)  \nCommentary  \nRestoring dendritic cell interstitial motility via PDE5 inhibition for sustained antitumor immunity✩  \nRuichen Zang1, Chen Zhang1, Guoqing Ding1,2,∗, Jie Zhang1,∗  \n1 Department of Urology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China  \n2 National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Sir Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China  \nIn a recent publication in Nature, Zhou and colleagues identified cyclic guanosine monophosphate (cGMP), a canonical phosphodiesterase 5 (PDE5) substrate, as a key modulator of dendritic cell (DC) interstitial motility through Rho kinase (ROCK)-dependent modulation of myosin-II activity.1 This finding suggests a novel and promising therapeutic strategy, as pharmacological inhibition of PDE5 through sildenafil restored migratory conventional DCs (mig-cDCs) homing to tumor draining lymph nodes (tdLNs) and antitumor effect. Notably, combination therapy with sildenafil and anti-PD-1 blockade demonstrates synergistic antitumor efficacy, surpassing monotherapy outcomes.  \nFunctioning as the sentinel of the immune system, DCs mainly sample, process and present antigens to T cells. A specialized subset of DCs called mig-cDCs in tumor microenvironment (TME) traverse tissues and emigrate through lymphatic vessels into tdLNs, where they cooperate with LN-resident cDCs to initiate robust tumor-specific T cell priming.2 The process of migration is driven by the actin-myosin complex and small GTPases, with spatiotemporal polarization of actin polymerization and myosin-II contractility establishing front-rear asymmetry.3 However, how DC interstitial motility is affected by TME and its impact on anti-tumor immunity remains unresolved.  \nZhou and colleagues revealed that mature DCs significantly decreased in tdLNs from patients with late-stage tumor, which strongly compromised tumor-specific T cell priming and proliferation.1 A twostage CRISPR screening strategy was then employed to investigate how the TME impaired DC interstitial motility and subsequent trafficking to tdLNs. At the first stage, a preliminary pre-round screen of genome-wide sgRNA library using injection with bone-marrow-derived DCs (BMDCs) differentiated ex vivo from lineage-negative bone marrow cells of Cas9-eGFP mice was adopted, which aimed to downsize the library and exclude genes that might impair DC development or viability. At the second stage, a definitive major-round screen of selected-minipool sgRNA library using BM reconstitution with hematopoietic stem and progenitor cells (HSPCs) from Zbtb46creCas9LSL donor mice was adopted, which better recapitulated DC ontogeny and trafficking within physiological condition and avoided technical artifacts associated with ex vivo BMDCs  \ndifferentiation procedures. Pde5 emerged as the top hit from both stage of screening, with ex vivo ear explants and 3D collagen gel system models further validating PDE5 as a negative regulator of DC interstitial motility.  \nMechanically, PDE5 selectively hydrolyzed cGMP, while cGMP enhanced the phosphorylation of the myosin light chain and myosin-II activity through the RhoA-ROCK-myosin light chain kinase (MLCK) pathway, which rendered contraction of actin bundles. Although Pde5 expression was unchanged between early- and late-stage tumoral DCs, significant downregulation of soluble guanylyl cyclase (sGC), which catalyzes the conversion of guanosine triphosphate (GTP) into cGMP, was observed in DCs from late-stage tumors. In fact, nitric oxide synthase- 2 (NOS2) expression substantially decreased as tumors advanced from early to late stage, and the reduction of NO biosynthesis led","cbCaiky5QsAveoUh","https://ap.wps.com/l/cbCaiky5QsAveoUh","pdf",310114,"English","# Commentary\n## Restoring dendritic cell interstitial motility via PDE5 inhibition for sustained antitumor immunity","[{\"question\":\"What key pathway links PDE5 to dendritic cell interstitial motility?\",\"answer\":\"The commentary describes cGMP as the canonical PDE5 substrate and links cGMP to ROCK-dependent modulation of myosin-II activity, establishing actin-myosin-driven front-rear asymmetry during DC migration.\"},{\"question\":\"How does PDE5 inhibition affect tumor immune responses?\",\"answer\":\"By preventing cGMP hydrolysis, sildenafil increases DC migration velocity and persistence, enabling migration to tumor draining lymph nodes and promoting tumor-specific T cell priming, activation, and improved tumor control.\"},{\"question\":\"Why does the combined treatment with sildenafil and anti-PD-1 perform better than monotherapy?\",\"answer\":\"The commentary reports synergistic antitumor efficacy, with combined therapy showing substantially higher cure rates than anti-PD-1 alone or sildenafil alone, revitalizing both DC function and T cell responses.\"}]","Restoring dendritic cell interstitial motility via PDE5 inhibition for sustained antitumor immunity - Commentary | PDF",1790669656]