Live imaging of neolymphangiogenesis identifies acute antimetastatic roles of dsRNA mimics

Long‐range communication between tumor cells and the lymphatic vasculature defines competency for metastasis in different cancer types, particularly in melanoma. Nevertheless, the discovery of selective blockers of lymphovascular niches has been compromised by the paucity of experimental systems for whole‐body analyses of tumor progression. Here, we exploit immunocompetent and immunodeficient mouse models for live imaging of Vegfr3‐driven neolymphangiogenesis, as a versatile platform for drug screening in vivo. Spatiotemporal analyses of autochthonous melanomas and patient‐derived xenografts identified double‐stranded RNA mimics (dsRNA nanoplexes) as potent inhibitors of neolymphangiogenesis, metastasis, and post‐surgical disease relapse. Mechanistically, dsRNA nanoplexes were found to exert a rapid dual action in tumor cells and in their associated lymphatic vasculature, involving the transcriptional repression of the lymphatic drivers Midkine and Vegfr3, respectively. This suppressive function was mediated by a cell‐autonomous type I interferon signaling and was not shared by FDA‐approved antimelanoma treatments. These results reveal an alternative strategy for targeting the tumor cell‐lymphatic crosstalk and underscore the power of Vegfr3‐lymphoreporters for pharmacological testing in otherwise aggressive cancers.