2026-04-29T04:09:47Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/270012025-12-11T01:21:16Zcom_20.500.12105_19586com_20.500.12105_2202col_20.500.12105_19587
Repisalud
author
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
2025-12-10T13:12:42Z
2025-12-10T13:12:42Z
2025-04
Nat Cancer. 2025 Apr;6(4):682-701.
https://hdl.handle.net/20.500.12105/27001
40155713
NATURE CANCER
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.
eng
Systemic rewiring of dendritic cells by melanoma-secreted midkine impairs immune surveillance and response to immune checkpoint blockade.
research article
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Systemic rewiring of dendritic cells_Nat Cancer_2025.pdf