The plasmacytoid dendritic cell paradox in cancer: impaired type I interferon responses in a nucleic acid-rich tumor microenvironment.

Plasmacytoid dendritic cells (pDCs) are specialized immune cells best known for their ability to produce large amounts of type I interferons (IFN-I) upon nucleic acid sensing through endosomal Toll-like receptors (TLR)-7/8 and 9. In tumors, the accumulation of nucleic acids (NAs) deriving from extensive cancer cell death would be expected to activate pDCs and induce IFN-I-mediated anti-tumor responses. However, tumor-infiltrating pDCs typically exhibit impaired IFN-I production and instead acquire immunosuppressive properties, revealing a paradox between NAs availability and pDC function within the tumor microenvironment (TME). In this review, we examine current knowledge and explore the mechanisms that may constrain IFN-I responses by pDCs, including chronic stimulation, alterations in TLR signaling and limited accessibility of tumor-derived NAs. We discuss key open questions regarding how tumor-associated signals may impair pDC responsiveness and contribute to their dysfunction, the nature and immunostimulatory potential of tumor-derived NAs, and their intracellular delivery. By highlighting these unresolved questions, we propose conceptual frameworks to better understand pDC biology in cancer and identify strategies to restore their IFN-I-mediated antitumor functions.