Issues

Although PD-1 blockade has become a mainstay treatment for melanoma, it is not always effective. In a patient with metastatic melanoma in which all tumors but one responded to PD-1 blockade, Gstalder and colleagues found that the tumor-suppressor gene FBXW7 had a loss-of-function mutation. In immuno-competent mice, Fbxw7 deficiency in melanomas disrupted double-stranded RNA (dsRNA)–sensing pathways, leading to alterations in the tumor immune microenvironment that included a decrease in the CD8⁺ T-cell infiltration that PD-1 blockade normally induces. Restoration of dsRNA sensing in these melanomas conferred sensitivity to anti–PD-1. This work suggests that reactivation of dsRNA-sensing pathways in patients with FBXW7-mutant melanoma may be therapeutically relevant. For more information, see the article by Gstalder and colleagues on page 1296.