2026-04-29T04:09:47Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/270012025-12-11T01:21:16Zcom_20.500.12105_19586com_20.500.12105_2202col_20.500.12105_19587

00925njm 22002777a 4500 dc Catena, Xavier author Contreras-Alcalde, Marta author Juan-Larrea, Naiara author Cerezo-Wallis, Daniela author Calvo, Tonantzin G author Mucientes, Cynthia author Olmeda, David author Suárez, Javier author Oterino-Sogo, Sergio author Martínez, Lola author Megías, Diego author Sancho, David author Tejedo, Cristina author Frago, Susana author Dudziak, Diana author Seretis, Athanasios author Stoitzner, Patrizia author Soengas, María S author 2025-04 Cutaneous melanomas express a high number of potential neoepitopes, yet a substantial fraction of melanomas shift into immunologically cold phenotypes. Using cellular systems, mouse models and large datasets, we identify the tumor-secreted growth factor midkine (MDK) as a multilayered inhibitor of antigen-presenting cells. Mechanistically, MDK acts systemically in primary tumors, lymph nodes and the bone marrow, promoting a STAT3-mediated impairment of differentiation, activation and function of dendritic cells (DCs), particularly, conventional type 1 DCs (cDC1s). Furthermore, MDK rewires DCs toward a tolerogenic state, impairing CD8 T cell activation. Downregulating MDK improves DC-targeted vaccination, CD40 agonist treatment and immune checkpoint blockade in mouse models. Moreover, we present an MDK-associated signature in DCs that defines poor prognosis and immune checkpoint blockade resistance in individuals with cancer. An inverse correlation between MDK- and cDC1-associated signatures was observed in a variety of tumor types, broadening the therapeutic implications of MDK in immune-refractory malignancies. Nat Cancer. 2025 Apr;6(4):682-701. https://hdl.handle.net/20.500.12105/27001 40155713 NATURE CANCER Systemic rewiring of dendritic cells by melanoma-secreted midkine impairs immune surveillance and response to immune checkpoint blockade.