%0 Journal Article
%A Wilgenbus, Petra
%A Pott, Jennifer
%A Pagel, Sven
%A Witzler, Claudius
%A Royce, Jennifer
%A Marini, Federico
%A Reyda, Sabine
%A Madhusudhan, Thati
%A Kindler, Thomas
%A Hausen, Anne
%A Gaida, Matthias M
%A Weiler, Hartmut
%A Ruf, Wolfram
%A Graf, Claudine
%T Coagulation proteases modulate nucleic acid uptake and cGAS-STING-IFN induction in the tumor microenvironment.
%J JCI insight
%V 10
%N 17
%@ 2379-3708
%C Ann Arbor, Michigan
%I JCI Insight
%M DKFZ-2025-01876
%P e190311
%D 2025
%X Malignancies increase the risk for thrombosis and metastasis dependent on complex interactions of innate immune cells, platelets, and the coagulation system. Immunosuppressive functions of platelets and macrophage-derived coagulation factors in the tumor microenvironment (TME) drive tumor growth. Here, we show that patients with malignancies and tumor-bearing mice have increased levels of coagulation factor (F) X-expressing circulating monocytes engaged in platelet aggregate formation. This interaction and resulting thrombin generation on platelets interferes with monocyte differentiation and antigen uptake of antigen-presenting cells (APCs). Myeloid cell-specific deletion of FX or abrogated FXa signaling via protease activated receptor 2 (PAR2) averts the suppressive activity of platelets on tumor cell debris uptake and promotes the immune stimulatory activity of APCs in the TME. Myeloid cell FXa-PAR2 signaling deficiency specifically enhances activation of the cGAS-STING-IFN-I pathway with a resulting expansion of antigen experienced progenitor exhausted CD8+ T cells. Pharmacological blockade of FXa with direct oral anticoagulants expands T cell priming-competent immune cells in the TME and synergizes with the reactivation of exhausted CD8+ T cells by immune checkpoint inhibitors for improved antitumor responses. These data provide mechanistic insights into the emerging clinical evidence demonstrating the translational potential of FXa inhibition to synergize with immunotherapy.
%K Tumor Microenvironment: immunology
%K Animals
%K Humans
%K Mice
%K Membrane Proteins: metabolism
%K Nucleotidyltransferases: metabolism
%K Neoplasms: immunology
%K Neoplasms: pathology
%K Signal Transduction
%K Blood Platelets: metabolism
%K Blood Platelets: immunology
%K Factor Xa: metabolism
%K Factor Xa: genetics
%K Female
%K Receptor, PAR-2: metabolism
%K Receptor, PAR-2: genetics
%K CD8-Positive T-Lymphocytes: immunology
%K Mice, Inbred C57BL
%K Monocytes: metabolism
%K Monocytes: immunology
%K Antigen-Presenting Cells: immunology
%K Male
%K Cancer immunotherapy (Other)
%K Coagulation (Other)
%K Immunology (Other)
%K Oncology (Other)
%K Platelets (Other)
%K Vascular biology (Other)
%K Membrane Proteins (NLM Chemicals)
%K Nucleotidyltransferases (NLM Chemicals)
%K STING1 protein, human (NLM Chemicals)
%K cGAS protein, human (NLM Chemicals)
%K Sting1 protein, mouse (NLM Chemicals)
%K Factor Xa (NLM Chemicals)
%K Receptor, PAR-2 (NLM Chemicals)
%K cGAS protein, mouse (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40694429
%R 10.1172/jci.insight.190311
%U https://inrepo02.dkfz.de/record/304484