Core Viewpoint - The study highlights the critical role of dendritic cell (DC) interstitial motility in sustaining anti-tumor immunity, revealing that impaired migration in a disordered tumor microenvironment (TME) promotes tumor immune evasion, while enhancing this motility offers promising directions for dendritic cell-centered immunotherapy [5][15]. Group 1: Research Findings - The research published by the team from Westlake University indicates a gradual decline in migratory conventional dendritic cells (mig-cDC) in tumor-draining lymph nodes (tdLN) during tumor progression, which hampers the initial activation of tumor-specific T cells and their subsequent delivery to the TME, leading to immune evasion [4][11]. - A genome-wide CRISPR screening identified phosphodiesterase 5 (PDE5) and its substrate cGMP as key regulators of dendritic cell migration, with late-stage tumors disrupting cGMP synthesis in dendritic cells, thereby reducing their migratory capacity [4][12]. - The use of the PDE5 inhibitor sildenafil was shown to restore cGMP levels and enhance the migration of mig-cDC to tdLN, thereby maintaining anti-tumor immunity [12][14]. Group 2: Mechanisms and Implications - The study elucidates the NOS2-NO-sGC-PDE5 signaling axis, which maintains cGMP levels and determines dendritic cell migration ability, emphasizing the importance of this pathway in anti-tumor immunity [13]. - Sildenafil, commonly known for treating erectile dysfunction, has been observed to have anti-tumor effects, which this research provides an immunological mechanism for, suggesting its potential in enhancing dendritic cell function in cancer therapy [14][15]. - The findings suggest that enhancing the interstitial motility of dendritic cells could be a promising strategy for developing dendritic cell-based immunotherapies, addressing the challenges posed by the TME [5][15].