Restoring dendritic cell interstitial motility via PDE5 inhibition for sustained antitumor immunity - Commentary

Sep 29, 2026

Uploaded by Sarah

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 blockade.

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Commentary

Restoring dendritic cell interstitial motility via PDE5 inhibition for sustained antitumor immunity

Journal of the National Cancer Center 5 (2025) 555–557 Contents lists available at ScienceDirect Journal of the National Cancer Center journal [homepage:](homepage: www.elsevier.com/locate/jncc)[ www.elsevier.com/locate/jncc](homepage: www.elsevier.com/locate/jncc) Commentary Restoring dendritic cell interstitial motility via PDE5 inhibition for sustained antitumor immunity✩ Ruichen Zang1, Chen Zhang1, Guoqing Ding1,2,∗, Jie Zhang1,∗ 1 Department of Urology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China 2 National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Sir Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China In 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. Functioning 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. Zhou 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 diﬀerentiation 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. Mechanically, 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

FAQs

What key pathway links PDE5 to dendritic cell interstitial motility?

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.

How does PDE5 inhibition affect tumor immune responses?

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.

Why does the combined treatment with sildenaﬁl and anti-PD-1 perform better than monotherapy?

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.

Sep 29, 2026

Uploaded by Sarah