Plasmacytoid dendritic cells in melanoma: can we revert bad into good?

Tumor-infiltrating plasmacytoid dendritic cells (pDCs) promote an immunosuppressive milieu that drives tumor growth in melanoma. This phenomenon typically results from the lack of appropriate pDC activation signals in the tumor microenvironment, but it is also actively controlled by tumor cells, which have evolved strategies to inhibit type I IFN production by pDCs. In this issue, Camisaschi et al. identify a new mechanism in which tumors avoid type I IFN production by triggering LAG-3-dependent activation of pDCs. Combination therapies that restore pDC functionality and trigger innate activation to produce type I IFN should be envisaged to induce effective antitumor immunity.